Piperidine derivatives having effects on serotonin related systems

ABSTRACT

The present invention provides the compounds of the following formula:                    
     Wherein the variables are as defined in the specification and a method for inhibiting the reuptake of seretonin, antagonizing the 5-HT 1A  receptor and antagonizing the 5-HT 2A  receptor which comprises administering to a subject in need of such treatment an effective amount of the compound of above formula.

This application is a 371 of PCT/US99/14732 Jun. 29, 1999 which claimsbenefit of Ser. No. 60/091,241 Jun. 30, 1998.

Pharmaceutical researchers have discovered in recent years that theneurons of the brain which contain monoamines are of extreme importancein a great many physiological processes which very strongly affect manypsychological and personality-affecting processes as well. Inparticular, serotonin (5-hydroxytryptamine; 5-HT) has been found to be akey to a very large number of processes which affect both physiologicaland psychological functions. Drugs which influence the function ofserotonin in the brain are accordingly of great importance and are nowused for a surprisingly large number of different therapies.

The early generations of serotonin-affecting drugs tended to have avariety of different physiological functions, considered from both themechanistic and therapeutic points of view. For example, many of thetricyclic antidepressant drugs are now known to be active as inhibitorsof serotonin and norepinephrine reuptake, and also to haveanticholinergic, antihistaminic or anti-a-adrenergic activity. Morerecently, it has become possible to study the function of drugs atindividual receptors in vitro or ex vivo, and it has also been realizedthat therapeutic agents free of extraneous mechanisms of action areadvantageous to the patient. Accordingly, the objective of research nowis to discover agents which affect only functions of serotonin.

The present invention provides compounds which have selective activityas antagonists and partial agonists of the serotonin-1_(A) receptor andthe serotonin-2_(A) receptor, and activity as inhibitors of serotoninreuptake. The best-known pharmaceutical with the latter efficacy isfluoxetine, and the importance of its use in the treatment of depressionand other conditions is extremely well documented and publicized. Recentscientific articles, for example, Artigas, TIPS, 14, 262 (1993), havesuggested that the efficacy of a reuptake inhibitor may be decreased bythe activation of serotonin-1_(A) receptors with the resultant reductionin the firing rate of serotonin neurons. Accordingly, present researchin the central nervous system is focusing on the effect of combiningreuptake inhibitors with compounds which affect the 5-HT_(1A) receptor.In addition, it has been suggested that a 5-HT_(2A) receptor antagonistwould provide treatment of depression with fewer side effects than atypical serotonin reuptake inhibitor.

Compounds exhibiting both serotonin reuptake inhibition activity and5-HT_(1A) antagonist activity have been described, for example in U.S.Pat. No. 5,576,321, issued Nov. 19, 1996. It has been found that thecompounds of the present invention are potent serotonin reuptakeinhibitors, antagonists of the 5-HT_(1A) receptor and antagonists of the5-HT_(2A) receptor.

The present invention provides compounds of formula I:

wherein:

X is O, S, NR, S(═O), or S(═O)₂;

Y is —C(═O)—, —CH(OH)—, —CH₂—, —C(═NOR), CHNR₇R, S, SO, or SO₂;

------- represents a single or a double bond;

n is 1, 2, 3 or 4;

R is H or C₁-C₆ alkyl;

R_(1a), R_(1b), R_(1c) and R₂ are each independently H, F, Cl, Br, I,OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio,phenyl, NO₂, —NR₇R₈, —C(═O)NR₇R₈, —NR7C(═O)R₈, CN or phenyl substitutedwith from 1 to 3 substituents selected from the group consisting of F,Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl,(C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN;

R₃ is H, OH, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, or(C₁-C₆)alkylthio;

R₄ is aryl, heterocycle, C₃-C₈ cycloalkyl, aryl substituted with from 1to 3 substituents selected from the group consisting of F, Cl, Br, I,OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio,phenyl, NO₂, NH₂, or CN; or heterocycle substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl,NO₂, NH₂, or CN;

R₅ is aryl, heterocycle, C₃-C₈ cycloalkyl, aryl substituted with from 1to 3 substituents selected from the group consisting of F, Cl, Br, I,OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; or heterocycle substitutedwith from 1 to 3 substituents selected from the group consisting of F,Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN;

R_(6a) and R_(6b) are each independently H or C₁-C₃ alkyl;

R₇ and R₈ are each independently H, C₁-C₆ alkyl, aryl or arylsubstituted with from 1 to 3 substituents selected from the groupconsisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN;

and the pharmaceutically acceptable salts thereof.

The present invention further provides a method of inhibiting thereuptake of serotonin and antagonizing the 5-HT_(1A) receptor whichcomprises administering to a subject in need of such treatment aneffective amount of a compound of formula I.

In addition, the present invention provides a method of inhibiting thereuptake of serotonin, antagonizing the 5-HT_(1A) receptor, andantagonizing the 5-HT_(2A) receptor, which comprises administering to asubject in need of such treatment an effective amount of a compound offormula I.

More particularly, the present invention provides a method foralleviating the symptoms caused by withdrawal or partial withdrawal fromthe use of tobacco or of nicotine; a method of treating anxiety; and amethod of treating a condition chosen from the group consisting ofdepression, hypertension, cognitive disorders, psychosis, sleepdisorders, gastric motility disorders, sexual dysfunction, brain trauma,memory loss, eating disorders and obesity, substance abuse,obsessive-compulsive disease, panic disorder and migraine; which methodscomprise administering to a subject in need of such treatment aneffective amount of a compound of formula I.

In addition, the present invention provides a method of potentiating theaction of a serotonin reuptake inhibitor comprising administering to asubject in need of such treatment a compound of formula I in combinationwith a serotonin reuptake inhibitor.

In addition, the invention provides pharmaceutical compositions ofcompounds of formula I, including the hydrates thereof, comprising, asan active ingredient, a compound of formula I in combination with apharmaceutically acceptable carrier, diluent or excipient. Thisinvention also encompasses novel intermediates, and processes for thesynthesis of the compounds of formula I.

The invention further provides intermediates of the formula:

wherein:

X is O, S, NR, S(═O), or S(═O)₂;

------- represents a single or a double bond;

R is H or C₁-C₆ alkyl;

R_(1a), R_(1b), R_(1c) and R₂ are each independently H, F, Cl, Br, I,OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio,phenyl, NO₂, —NR₇R₈, —C(═O)NR₇R₈, —NR₇C(═O)R₈, CN or phenyl substitutedwith from 1 to 3 substituents selected from the group consisting of F,Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl,(C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN;

R_(6a), and R_(6b) are each independently H or C₁-C₃ alkyl;

R₇ and R₈ are each independently H, C₁-C₆ alkyl, aryl or arylsubstituted with from 1 to 3 substituents selected from the groupconsisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN.

In addition, the invention further provides intermediates of theformula:

wherein:

X is O, S, NR, S(═O), or S(═O)₂;

------- represents a single or a double bond;

R is H or C₁-C₆ alkyl;

R_(1a), R_(1b), R_(1c) and R₂ are each independently H, F, Cl, Br, I,OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio,phenyl, NO₂, —NR₇R₈, —C(═O)NR₇R₈, —NR₇C(═O)R₈, CN or phenyl substitutedwith from 1 to 3 substituents selected from the group consisting of F,Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl,(C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN;

R_(6a) and R_(6b) are each independently H or C₁-C₃ alkyl;

R₇ and R₈ are each independently H, C₁-C₆ alkyl, aryl or arylsubstituted with from 1 to 3 substituents selected from the groupconsisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN.

According to another aspect, the present invention provides the use of acompound of formula I for the manufacture of a medicament for inhibitingthe reuptake of serotonin, antagonizing the 5-HT_(1A) receptor, andantagonizing the 5-HT_(2A) receptor.

In addition, the present invention provides the use of a compound offormula I for inhibiting the reuptake of serotonin, antagonizing the5-HT_(1A) receptor, and antagonizing the 5-HT_(2A) receptor.

As used herein, an acyclic or cyclic acetal or ketal is represented bythe following:

and corresponds for example, to the following groups:

As used herein the term “Pg” refers to a protecting group on the aminewhich are commonly employed to block or protect the amine while reactingother functional groups on the compound. Examples of protecting groups(Pg) used to protect the amino group and their preparation are disclosedby T. W. Greene, “Protective Groups in Organic Synthesis,” John Wiley &Sons, 1981, pages 218-287. Choice of the protecting group used willdepend upon the substituent to be protected and the conditions that willbe employed in subsequent reaction steps wherein protection is required,and is well within the knowledge of one of ordinary skill in the art.Preferred protecting groups are t-butoxycarbonyl also known as a BOCprotecting group, and benzyloxycarbonyl.

As used herein, the terms “Halo”, “Halide” or “Hal” refers to achlorine, bromine, iodine or fluorine atom, unless otherwise specifiedherein.

As used herein, the term “Me” refers to a methyl group, the term “Et”refers to an ethyl group, the term “Pr” refers to a propyl group, theterm “iPr” refers to an isopropyl group, “Bu” refers to a butyl group,and the term “Ph” refers to a phenyl group.

As used herein the term “serotonin” is equivalent to and interchangeablewith the terms “5-HT” or “5-hydroxytryptamine”.

As used herein the term “C₁-C₆ alkyl” refers to straight or branched,monovalent, saturated aliphatic chains of 1 to 6 carbon atoms andincludes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term “C₁-C₆alkyl” includes within its definition the term “C₁-C₄ alkyl”.

As used herein the term “halo(C₁-C₆)alkyl” refers to a straight orbranched alkyl chain having from one to six carbon atoms with 1, 2 or 3halogen atoms attached to it. Typical halo(C₁-C₆)alkyl groups includechloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl,2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl andthe like. The term “halo(C₁-C₆)alkyl” includes within its definition theterm “halo(C₁-C₄)alkyl”.

As used herein the term “hydroxy(C₁-C₆)alkyl” refers to a straight orbranched alkyl chain having from one to six carbon atoms with a hydroxygroup attached to it, such as —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, and thelike. The term “hydroxy(C₁-C₆)alkyl” includes within its definition theterm “hydroxy(C₁-C₄)alkyl”.

As used herein the term “(C₁-C₆)alkylthio” refers to a straight orbranched alkyl chain having from one to six carbon atoms attached to asulfur atom. Typical (C₁-C₆)alkylthio groups include —SCH₃, —SCH₂CH₃,—S(CH₂)₂CH₃, —S(CH₂)₃CH₃, —S(CH₂)₄CH₃, —S(CH₂)₅CH₃, and the like. Theterm “(C₁-C₆)alkylthio” includes within its definition the term“(C₁-C₄)alkylthio”.

As used herein the term “C₁-C₆ alkoxy” refers to a straight or branchedalkyl chain having from one to six carbon atoms attached to an oxygenatom. Typical C₁-C₆ alkoxy groups include methoxy, ethoxy, propoxy,isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term “C₁-C₆alkoxy” includes within its definition the term “C₁-C₄ alkoxy”.

As used herein the term “hydroxy(C₁-C₆)alkyl” refers to a straight orbranched alkyl chain having from one to six carbon atoms with a hydroxygroup attached to it. Typical hydroxy(C₁-C₆)alkyl groups includehydroxymethyl, 2-hydroxyethyl, 1-hydroxyisopropyl, 2-hydroxypropyl,2-hydroxybutyl, 3-hydroxyisobutyl, hydroxy-t-butyl, 1-hydroxypentyl,1-hydroxyhexyl and the like. The term “hydroxy(C₁-C₆)alkyl” includeswithin its definition the term “hydroxy(C₁-C₄)alkyl”.

As used herein the term “C₃-C₈ cycloalkyl” refers to a saturatedhydrocarbon ring structure containing from three to eight carbon atoms.Typical C₃-C₈ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

As used herein the term “aryl” refers to a phenyl or naphthyl group.

As used herein the term “heterocycle” refers to a stable 5- to7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ringwhich is saturated or unsaturated, and consists of carbon atoms and fromone to three heteroatoms selected from the group consisting of nitrogen,oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequaternized and including a bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichaffords a stable structure.

Examples of such heterocycles include piperidinyl, piperazinyl,azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, pyridyl, pyridyl N-oxide, pyrazinyl,pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolyl,furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl,thiamorpholinyl, thiamorpholinyl-sulfoxide, thiamorpholinylsulfone,oxadiazolyl, triazolyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl,and the like.

As used herein, the following numbering system applies to the bicyclicportion of formula I as follows:

In addition, it is appreciated by one of ordinary skill in the art thatformula I encompasses the following structures:

This invention includes the hydrates and the pharmaceutically acceptablesalts of the compounds of formula I. A compound of this invention canpossess a sufficiently basic functional group which can react with anyof a number of inorganic and organic acids, to form a pharmaceuticallyacceptable salt.

The term “pharmaceutically acceptable salt” as used herein, refers tosalts of the compounds of formula I which are substantially non-toxic toliving organisms. Typical pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds of the presentinvention with a pharmaceutically acceptable mineral or organic acid.Such salts are also known as acid addition salts.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide,acetate, propionate, decanoate, caprylate, acrylate, formate,hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, g-hydroxybutyrate, glycolate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,napththalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid, oxalic acid andmethanesulfonic acid.

It should be recognized that the particular counterion forming a part ofany salt of this invention is usually not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole. It is further understood that such salts may exist as a hydrate.

As used herein, the term “stereoisomer” refers to a compound made up ofthe same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

The term “enantiomeric enrichment” as used herein refers to the increasein the amount of one enantiomer as compared to the other. A convenientmethod of expressing the enantiomeric enrichment achieved is the conceptof enantiomeric excess, or “ee”, which is found using the followingequation: ${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$

wherein E¹ is the amount of the first enantiomer and E² is the amount ofthe second enantiomer. Thus, if the initial ratio of the two enantiomersis 50:50, such as is present in a racemic mixture, and an enantiomericenrichment sufficient to produce a final ratio of 50:30 is achieved, theee with respect to the first enantiomer is 25%. However, if the finalratio is 90:10, the ee with respect to the first enantiomer is 80%. Anee of greater than 90% is preferred, an ee of greater than 95% is mostpreferred and an ee of greater than 99% is most especially preferred.Enantiomeric enrichment is readily determined by one of ordinary skillin the art using standard techniques and procedures, such as gas or highperformance liquid chromatography with a chiral column. Choice of theappropriate chiral column, eluent and conditions necessary to effectseparation of the enantiomeric pair is well within the knowledge of oneof ordinary skill in the art. In addition, the enantiomers of compoundsof formulas I or Ia can be resolved by one of ordinary skill in the artusing standard techniques well known in the art, such as those describedby J. Jacques, et al., “Enantiomers, Racemates, and Resolutions”, JohnWiley and Sons, Inc., 1981. Examples of resolutions includerecrystallization techniques or chiral chromatography.

Some of the compounds of the present invention have one or more chiralcenters and may exist in a variety of stereoismeric configurations. As aconsequence of these chiral centers, the compounds of the presentinvention occur as racemates, mixtures of enantiomers and as individualenantiomers, as well as diastereomers and mixtures of diastereomers. Allsuch racemates, enantiomers, and diastereomers are within the scope ofthe present invention.

The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

As used herein, the term “SRI” refers to serotonin reuptake inhibitor.

The compounds of formula I can be prepared by techniques and proceduresreadily available to one of ordinary skill in the art, for example byfollowing the procedures as set forth in the following Schemes. Theseschemes are not intended to limit the scope of the invention in any way.All substituents, unless otherwise indicated, are previously defined.The reagents and starting materials are readily available to one ofordinary skill in the art. Scheme I provides a synthesis of compounds ofstructure (8).

In Scheme I, step A, the compound of structure (1) is alkylated with acompound of structure (2) under conditions well known in the art. Forexample, compound (1) is dissolved in a suitable organic solvent, suchas dimethylformamide (DMF) or tetrahydrofuran (THF). Examples ofcompound (1) include 2-bromothiophenol, 2-bromophenol,2-bromo-3-fluorophenol, 2-bromo-4-fluorophenol, 2-bromo-5-fluorophenol,2-chloro-4-(1,1-dimethylethyl)phenol, 2-bromo-5-chlorophenol,3-bromo-4-hydroxybenzonitrile, 2-chloro-4-(tert-phenyl)phenol,2-chloro-5-(trifluoromethyl)phenol, 3-chloro-4-hydroxy-benzotrifluoride,2-chloro-4-nitrophenol, 3-chloro-4-biphenylol,3-bromo-4-hydroxybiphenyl, 2-chloro-4-fluorothiophenol,2-chloro-4-methylphenol, 2-chloro-4-methoxyphenyl,2-chloro-5-methoxyphenol, 2-bromo-4-methylphenol,2-chloro-5-methylphenol, 4-bromoresorcinol, 4-chlororesorcinol,2-bromo-4-chlorophenol, and the like. As used in Scheme I, Halrepresents Cl, Br or I only, and X represents S, O or NR. The solutionis treated with a slight excess of a suitable base, such as potassiumcarbonate or sodium hydride followed by addition of about 1.05 to about1.20 equivalents of compound (2). Examples of compound (2) includebromoacetaldehyde diethyl acetal, 2-bromomethyl-1,3-dioxolane and thelike. The reaction mixture is then stirred at room temperature to refluxfor about 1 to 7 hours. The product is then isolated and purified byextraction techniques and chromatography. For example, the reaction isdiluted with water and extracted with a suitable organic solvent, suchas ethyl acetate. The organic extracts are combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue is then purified by flash chromatography on silica gel with asuitable eluent, such as ethyl acetate/hexane to provide compound (3).

In Scheme I, step B, compound (3) is cyclized to the compound ofstructure (4) under acidic conditions. For example, compound (3) isdissolved in a suitable organic solvent, such as chlorobenzene and thesolution is added dropwise to a refluxing mixture of polyphosphoric acidand chlorobenzene. The reaction mixture is heated at reflux for about 2to 5 hours and then cooled to room temperature. The compound (4) is thenisolated and purified by techniques well known in the art. For example,the reaction mixture is made slightly basic with 1N sodium hydroxide andthen extracted with a suitable organic solvent, such as ethyl acetate.The organic extracts are combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue is then purified byflash chromatography on silica gel with a suitable eluent, such ashexane or ethyl acetate/hexane to provide the compound (4).

In Scheme I, step C, compound (4) undergoes an aldol reaction with thepiperidone of structure (5) under standard conditions well known in theart, such as Grignard Type conditions (See for example J. March,“Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,”2^(nd) Edition, McGraw-Hill, 1977, 836-841), to provide the alcohol ofstructure (6). For example, compound (4) is dissolved in a suitableorganic solvent, such as diethyl ether and the solution is addeddropwise to a mixture of about 2 equivalents of magnesium suspended indiethyl ether. If necessary, about 1 equivalent of dibromoethane is thenadded and the reaction is heated to reflux for about 1 to 5 hours. Thereaction is then cooled to room temperature and about 1 equivalent ofthe piperidone (5) is added to the prepared Grignard reagent. Thereaction is then allowed to stir at room temperature for about 5 to 18hours. The reaction is quenched by addition of water and the alcohol (6)is isolated and purified by techniques well known in the art. Forexample, the quenched reaction is extracted with a suitable organicsolvent, such as diethyl ether, the organic extracts are combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue is then purified by flash chromatography on silica gel witha suitable eluent, such as ethyl acetate/hexane to provide alcohol (6).

In Scheme I, step D, alcohol (6) is deprotected and dehydrated understandard conditions well known in the art to provide to provide the1,2,3,6-tetrahydropyridine of structure (7). One of ordinary skill inthe art would readily appreciate that deprotection and dehydration canbe carried out in a stepwise fashion, in any order, or concomitantly.For example, step D is carried out concomitantly by dissolving thealcohol (6) in a suitable organic solvent, such as toluene and treatingthe solution with an excess of a suitable acid, such asp-toluenesulfonic acid. The reaction is heated at reflux for about 1 to4 hours, then cooled and the solution is made basic with a suitablebase, such as 1N sodium hydroxide. The 1,2,3,6-tetrahydropyridine (7) isthen isolated and purified by techniques well known in the art. Forexample, the solution is extracted with a suitable organic solvent, suchas ethyl acetate, the organic extracts are combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue can then be purified if necessary by flash chromatography onsilica gel with a suitable eluent, such as ethyl acetate/hexane toprovide 1,2,3,6-tetrahydropyridine (7).

In Scheme I, step E, 1,2,3,6-tetrahydropyridine (7) can be hydrogenatedunder conditions well known in the art to provide the piperidine ofstructure (8). For example, the 1,2,3,6-tetrahydropyridine (7) isdissolved in a suitable organic solvent, such as absolute ethanol, andtreated with a suitable hydrogenation catalyst, such as 10% palladium oncarbon. The reaction mixture is then treated with an excess of ammoniumformate and the reaction is heated at reflux for about 2 to 4 hours. Thereaction mixture is then cooled, filtered to remove the catalyst and thefiltrate is concentrated under vacuum to provide piperidine (8). Thepiperidine (8) can be purified by flash chromatography on silica gelwith a suitable eluent, such as ethyl acetate/hexane. Alternatively, theresidue can be converted to a pharmaceutically acceptable salt, such asthe oxalate salt by dissolving the residue in methanol, treating with 1equivalent of oxalic acid and then concentrating the solution undervacuum. The solid can then be purified by recrystallization from asuitable organic solvent, such as diethyl ether to provide the purifiedoxalate salt of piperidine (8).

Scheme IA provides an alternative synthesis for the preparation ofcompound (4).

In Scheme IA, step A, compound (1) is alkylated with a compound ofstructure (9) in a manner analogous to the procedure described above inScheme I, step A to provide the alkylated compound of structure (10). Asused in Scheme IA, Hal represents Cl, Br or I only, and X represents S,O or NR. For example, compound (1) is dissolved in a suitable organicsolvent, such as tetrahydrofuran and a slight excess of a suitable base,such as potassium carbonate. The mixture is then treated with about 1.05to 1.2 equivalents of compound (9), such as ethyl 2-bromopropionate, anda catalytic amount of potassium iodide, and the reaction is heated atreflux for about 2 to 5 hours. The reaction is then cooled, diluted withwater and extracted with a suitable organic solvent, such as ethylacetate. The organic extracts are combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue is purifiedby flash chromatography on silica gel with a suitable eluent, such asethyl acetate/hexane to provide alkylated compound (10).

In Scheme IA, step B, alkylated compound (10) is reduced to the aldehydeof structure (11) under conditions well known in the art. For example,the alkylated compound (10) is dissolved in a suitable organic solvent,such as toluene and cooled to about −78° C. The cooled solution is thentreated dropwise with about 1.00 -1.05 equivalents of a suitablereducing agent, such as diisobutylaluminum hydride in toluene. Thereaction is then stirred for about 20 to 60 minutes at −78° C. and thenquenched with methanol. After warming to room temperature, the reactionis treated with saturated sodium tartrate solution and stirred for about30 minutes. The mixture is then extracted with a suitable organicsolvent, such ethyl acetate. The organic extracts are combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum toprovide aldehyde (11).

In Scheme IA, step C the aldehyde (11) is cyclized to the compound ofstructure (4) in a manner analogous to the procedure described above inScheme I, step B.

Scheme II provides an alternative synthesis of compound (7).

In Scheme II, step A, protected piperidone (5) is converted to the tinderivative (12) under conditions well known in the art. For example,diisopropylamine is dissolved in a suitable organic solvent, such astetrahydrofuran and the solution is cooled to about 0° C. An equivalentof n-butyllithium is added and the reaction is stirred for about 15minutes to one hour. Then one equivalent of tri-n-butyltinhydride isadded dropwise to the solution, the reaction mixture is stirred forabout one hour and then cooled to about −78° C. To this reaction mixtureis added dropwise about 0.85 equivalents of the protected piperidone (5)dissolved in tetrahydrofuran. The reaction is then stirred for about 1to 5 hours at −78° C. and then quenched with buffer (pH 6). The reactionmixture is extracted with a suitable organic solvent, such as ethylacetate, the organic extracts are combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue is purifiedby flash chromatography on silica gel with a suitable eluent, such asethyl acetate/hexane to provide the tin derivative (12).

In Scheme II, step B, tin derivative (12) is dehydrated to the1,2,3,6-tetrahydropyridine (13) under standard conditions. For example,the tin derivative (12) is dissolved in a suitable organic solvent, suchas methylene chloride and the solution is cooled to about 0° C. Anexcess of triethylamine and about 2.0 equivalents of methanesulfonylchloride are added to the solution which is allowed to stir for about 4to 20 hours. The reaction mixture is warmed to room temperature andconcentrated under vacuum. The residue is purified by flashchromatography on silica gel with a suitable eluent, such as ethylacetate/hexane to provide the 1,2,3,6-tetrahydropyridine (13).

In Scheme II, step C the 1,2,3,6-tetrahydropyridine (13) is coupled withcompound (4), prepared in Scheme I, to provide the compound of structure(14). For example, one equivalent of compound (4) and one equivalent of1,2,3,6-tetrahydropyridine (13) are combined in a suitable organicsolvent, such as toluene. A catalytic amount of2,6-di-tert-butyl-4-methylphenol and a catalytic amount oftetrakis(triphenylphosphine)palladium(0) are added and the reactionmixture is heated at reflux for about 15 to 20 hours. The reactionmixture is then cooled, concentrated under vacuum and the residuepurified by flash chromatography on silica gel with a suitable eluent,such as ethyl acetate/hexane to provide compound (14).

In Scheme II, step D, compound (14) is deprotected under conditions wellknown in the art to provide the compound of structure (7). For example,compound (14) is dissolved in a suitable organic solvent, such astoluene and treated with a suitable acid, such a p-toluenesulfonic acid.The reaction is heated at reflux for about 1 to 2 hours, then cooled toroom temperature. The mixture is diluted with a suitable organicsolvent, such as ethyl acetate, washed with sodium hydroxide solution,the organic layer is dried over anhydrous sodium sulfate, filtered andconcentrated to provide compound (7).

Scheme III provides a synthesis of the aldehydes of structure (20).

In Scheme III, step A, the compound of structure (15) is alkylated withthe compound of structure (16) to provide the compound of structure (17)under conditions well known in the art. When G is hydrogen and R₄ is2-pyridyl, 3-pyridyl or 4-pyridyl, for example, then a base, such asn-butyllithium is used to prepare the corresponding anion which isreacted with compound (16). For example, compound (15) is dissolved in asuitable organic solvent, such as tetrahydrofuran and cooled to about−78° C. About 1.1 equivalents of n-buytllithium is added to the cooledsolution which is then allowed to warm to room temperature over onehour. The solution is then re-cooled to about −78° C. and treateddropwise with about 1.05 equivalents of a compound of structure (16)dissolved in tetrahydrofuran. [Compounds of structure 16 are readilyprepared by one of ordinary skill in the art following generally theprocedure disclosed by Brornidge, S. M., et al., SyntheticCommunications, 23(4), 487-494 (1993).] The reaction is then allowed towarm to room temperature and stirred for about 20 to 40 hours. Thereaction mixture is then diluted with water and dilute acid maintaininga pH of about 12. The quenched reaction is then extracted with asuitable organic solvent, such as methylene chloride, the organicextracts are combined, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue is then purified by flashchromatography on silica gel with a suitable eluent, such as ethylacetate/hexane to provide the compound (17).

Alternatively, when G is Cl or Br and R₄ is aryl, for example, aGrignard reagent is prepared, using techniques and procedures well knownin the art, from magnesium in a suitable organic solvent, such asdiethyl ether or tetrahydrofuran and refluxing as necessary. Theresulting Grignard reagent is then combined with the compound (16) toprovide compound (17).

In Scheme III, step B, compound (17) is alkylated with a compound ofstructure (18) to provide the compound of structure (19) underconditions well known in the art. For purposes of Scheme III, Halrepresents Cl, Br or I. For example, compound (17) is dissolved in asuitable organic solvent and treated with a suitable base. Examples ofsuitable organic solvents are tetrahydrofuran, methyl sulfoxide,dimethylformamide, methyl sulfoxide/tetrahydrofuran,dimethylformamide/tetrahydrofuran, and the like. Examples of suitablebases are potassium tert-butoxide, n-butyllithium, sodium hydride, andthe like. For example, compound (17) is dissolved in tetrahydrofuran,and the solution is added dropwise to a cooled suspension (0° C.) of 1.4equivalents of sodium hydride in tetrahydrofuran. The reaction is warmedto room temperature and stirred for about 2 to 4 hours. Then about 1.5equivalents of a compound (18) is added to the reaction which is thenheated at reflux for about 16 hours. The reaction is then diluted withwater, extracted with a suitable eluent, such as diethyl ether, theorganic extracts are combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue is purified by flashchromatography on silica gel with a suitable eluent, such as ethylacetate/hexane to provide compound (19).

In Scheme III, step C, compound (19) is hydrolyzed under conditions wellknown in the art to provide the aldehyde of structure (20). For example,compound (19) is dissolved in a suitable organic solvent, such asacetone and treated with an excess of a suitable acid, such as 3N HCl.The reaction is stirred at room temperature for about 10 to 20 hours. Itis then neutralized with a suitable base, such as 1 N sodium hydroxide.The neutralized mixture is then extracted with a suitable organicsolvent, such as ethyl acetate, the organic extracts are combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum toprovide the aldehyde (20).

Scheme IV provides a synthesis of compounds of formulas Ia through Id.All substituents, unless otherwise specified, are previously defined.The reagents and starting materials are readily available to one ofordinary skill in the art.

In Scheme IV, step A, compounds (7) or (8), prepared in Scheme I above,are subjected to a reductive alkylation with compound (20), prepared inScheme III above, under conditions well known in the art, such as thosedisclosed in J. March, “Advanced Organic Chemistry: Reactions,Mechanisms and Structure”, 2^(nd) Edition, McGraw-Hill, 1978, 819-820,to provide the compound of formula (Ia). For example, in Scheme IV, stepA, about one equivalent of either compound (7) or (8) is combined withone equivalent of compound (20) in a suitable organic solvent, such asmethylene chloride. To this solution is added about 2.5 equivalents ofacetic acid and about 1.3 equivalents of sodium triacetoxyborohydride.The reaction is stirred at room temperature for about 4 to 24 hours andthen made basic with 1N sodium hydroxide. The mixture is then extractedwith a suitable organic solvent, such as methylene chloride, thecombined organic extracts are dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to provide the crude compound offormula Ia. This material can be purified by techniques well known inthe art. For example, the crude material is purified by flashchromatography on silica gel with a suitable eluent such as ethylacetate/hexane. The purified compound of formula Ia can then beconverted to the pharmaceutically acceptable salt, such as the oxalatesalt by dissolving in methanol and treating with one equivalent ofoxalic acid. The solvent is then removed under vacuum to provide theoxalate salt of formula Ia. The oxalate salt can be further purified byrecrystallization from suitable organic solvents, such as methylenechloride and hexane.

Alternatively, the crude compound of formula Ia can be purified bydirect conversion of the crude free base to the pharmaceuticallyacceptable salt, such as the oxalate salt, and recrystallized from asuitable organic solvent, such as methylene chloride and hexane.

In Scheme IV, step B, formula Ia is hydrogenated under conditions wellknown in the art to provide the compound of formula Ib. For example,compound of formula Ia is dissolved in absolute ethanol and treated with10% palladium on carbon. The reaction is stirred under an atmosphere ofhydrogen for about 1 to 24 hours. The reaction is then filtered toremove the catalyst and the filtrate is concentrated under vacuum. Theresidue is purified by techniques well known in the art, such as thosedescribed in step A above to provide the compound of formula Ib aseither the free base or a pharmaceutically acceptable salt.

In Scheme IV, step D, formula Ib is further reduced under conditionswell known in the art to provide the compound of formula Ic. Forexample, the compound of formula Ib is dissolved in a suitable organicsolvent such as methylene chloride, cooled to about −78° C. and treatedwith a suitable reducing agent, such as about 3 equivalents ofdiisobutylaluminum hydride or lithium aluminum hydride. The reaction isthen slowly warmed to room temperature over about 2 hours and thenstirred at room temperature for about 16 hours. The reaction is thendiluted with saturated aqueous potassium sodium tartrate solution andextracted with methylene chloride. The organic extracts are combined,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue is purified by flash chromatography on silica gelwith a suitable eluent, such as ethyl acetate/hexane to provide the freebase of the compound of formula Ic. As described above in step A, thisfree base can then be converted to the pharmaceutically acceptable salt,such as an oxalate salt.

In Scheme IV, step C the compound of formula Ia is reduced to thecompound of formula Id in a manner analogous to the procedure describedabove in step D. In addition, the free base of formula Id is convertedto the pharmaceutically acceptable salt in a manner analogous to theprocedure described in step A above.

Scheme V provides a synthesis of the compound of formula Ie. Reagentsand starting materials are readily available to one of ordinary skill inthe art. All substituents are previously defined, unless otherwiseindicated.

In Scheme V, step A, a compound of structure (21) is alkylated with acompound of structure (22) under conditions well known in the art toprovide the compound of structure (23). When G is hydrogen and R₄ is2-pyridyl, 3-pyridyl or 4-pyridyl, for example, then a base, such asn-butyllithium is used to prepare the corresponding anion which isreacted with compound (22). For example, compound (21) is dissolved in asuitable organic solvent, such as THF and treated with a suitable base,such as n-butyllithium at about −78° C. The mixture is warmed to roomtemperature and then cooled back down to −78° C. and treated with about1.05 equivalents of a compound (22), wherein for the purposes of SchemeV, Hal represents Cl, Br or I. The reaction is warmed to roomtemperature and allowed to stir for 10 to 20 hours. It can then beheated to reflux for about 2 to 24 hours and then cooled to roomtemperature. The solvent is then removed under vacuum, the residuedissolved in a suitable organic solvent, such as ethyl acetate, followedby addition of water. The layers are separated, and the aqueous isextracted with ethyl acetate. The organic extracts are combined, driedover anhydrous magnesium sulfate, filtered and concentrated undervacuum. The residue is purified by flash chromatography on silica gelwith a suitable eluent, such as ethyl acetate/hexane to provide compound(23).

Alternatively, when G is Cl or Br and R₄ is aryl, for example, aGrignard reagent is prepared, using techniques and procedures well knownin the art, from magnesium in a suitable organic solvent, such asdiethyl ether or tetrahydrofuran and refluxing as necessary. Theresulting Grignard reagent is then combined with the compound (22) understandard conditions to provide compound (23). Additional conditions forcoupling of alkyl halides with organometallic reagents, can be found inJ. March, “Advanced Organic Chemistry: Reactions, Mechanisms andStructure”, 2nd Edition, McGraw-Hill, 1978, pages 409-412.

In Scheme V, step B, compound (23) is alkylated with compound (18) in amanner analogous to the procedure described in Scheme III, step B toprovide the compound of structure (24). As used herein, Hal representsCl, Br or I only.

In Scheme V, step C, compound (24) is hydrolyzed under acidic conditionsin a manner analogous to the procedure described in Scheme III, step Cto provide the aldehyde of structure (25).

In Scheme V, step D, compound (25) is used to reductively alkylate withcompound (7) [prepared in Scheme I or II above] or compound (8)[prepared in Scheme I above], in a manner analogous to the proceduredescribed in Scheme IV, step A to provide the compound of formula Ie.

Compounds wherein X is S(═O) or S(═O)₂ in formula I are readily preparedby one of ordinary skill in the art using well known techniques andprocedures. For example, compounds of formulas Ia-Ie wherein X is S canbe oxidized under standard conditions, such as treatment withm-chloroperbenzoic acid, to provide the corresponding sulfone [S(═O)₂]or sulfoxide [S(═O)].

Intermediate aldehyde of structure (20a) can be prepared as described inScheme VI below. Aldehyde (20a) is reductively aminated in a manneranalogous to aldehyde (20) to provide compound of formula I. Thereagents and starting materials are readily available to one of ordinaryskill in the art.

In Scheme VI, step A, aldehyde (26) is combined with a suitableorganometallic reagent (27) under conditions well known in the art toprovide alcohol (28). Examples of suitable organometallic reagentsinclude Grignard Reagents, alkyl lithium reagents, and the like.Grignard Reagents are preferred. For examples of typical GrignardReagents and reaction conditions, see J. March, “Advanced OrganicChemistry: Reactions, Mechanisms, and Structure”, 2nd Edition,McGraw-Hill, pages 836-841 (1977). More specifically, aldehyde (26) isdissolved in a suitable organic solvent, such as tetrahydrofuran, cooledto about −5° C. and treated with about 1.1 to 1.2 equivalents of aGrignard reagent of formula (27) wherein M is MgCl or MgBr. The reactionis allowed to stir for about 1 to 2 hours, then quenched, and alcohol(28) is isolated. For example, the reaction mixture is poured ontoice-cold 1N HCl, the quenched mixture is extracted with a suitableorganic solvent, such as toluene, the organic extracts are dried overanhydrous magnesium sulfate, filtered and concentrated under vacuum toprovide alcohol (28).

In Scheme VI, step B, alcohol (28) is oxidized under standard conditionswell know in the art, such as those described by J. March, “AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure”, 2nd Edition,McGraw-Hill, pages 1082-1084 (1977), to provide ketone (29).

For example, alcohol (28) is dissolved in a suitable organic solvent,such as methylene chloride, the solution cooled with a wet ice-acetonebath, and treated with 2.5 to 3.0 equivalents of dimethyl sulfoxide.After stirring for about 30 minutes, the reaction is then treated withabout 1.8 equivalents of P2O5. The reaction is allowed to stir for about3 hours and then is treated over about 30 minutes with about 3.5equivalents of a suitable amine, such as triethylamine. The cooling bathis then removed and the reaction is allowed to stir for about 8 to 16hours. The ketone (29) is then isolated by standard extractiontechniques well known in the art.

In Scheme VI, step C, ketone (29) is treated with a suitable basefollowed by addition of the alkene (30), wherein X is a suitable leavinggroup, to provide compound (31). For example, ketone (29) is combinedwith an excess of alkene (30) in a suitable organic solvent, such astetrahydrofuran, and cooled with a wet ice acetone bath. Examples ofsuitable leaving groups are Cl, Br, I, and the like. Preferred leavinggroups are Cl and Br. About 1.1 equivalents of a suitable base, such aspotassium tert-butoxide, is added and the reaction is allowed to stirfor about 2 hours at room temperature. The reaction is then quenchedwith aqueous acid and compound (31) is isolated by extraction withheptane. The heptane extracts are washed with sodium bicarbonate, driedover anhydrous magnesium sulfate, filtered and concentrated under vacuumto provide compound (31).

In Scheme VI, step D, compound (31) is treated with a suitable oxidizingagent to provide aldehyde (20a). Ozone is the preferred oxidizing agent.Examples of suitable oxidizing reagents and conditions are described byJ. March, “Advanced Organic Chemistry: Reactions, Mechanisms, andStructure”, 2nd Edition, McGraw-Hill, pages 1090-1096 (1977).

For example, compound (31) is dissolved in a suitable organic solvent,such as methanol, a small amount of Sudan III is added, and the solutionis cooled to about −20° C. Ozone is bubbled into the solution for about4 hours until the pink color turns to a pale yellow color. Then Me₂S isadded to the reaction mixture and the cooling bath is removed.Concentration of the reaction mixture under vacuum provides theintermediate dimethyl acetal of aldehyde (20a). This dimethyl acetal isreadily hydrolyzed under standard acidic conditions to provide aldehyde(20a). Alternatively, direct acidic work-up of the crude reactionmixture provides aldehyde (20a).

The compounds of formulas If, Ig, Ih and Ij can be prepared as describedin Scheme VII. The reagents and starting materials are readily availableto one of ordinary skill in the art. Unless otherwise specified, thesubstituents are as previously defined.

In Scheme VII, step A, the compounds of formula Ia or formula Ib areconverted to the corresponding oxime of formulas If and Ig underconditions well known in the art. For example, the compounds of formulaIa or Ib are dissolved in a suitable solvent or solvent mixture, such asethanol/water and treated with an excess of a suitable hydroxylamine,such as hydroxylamine hydrochloride. The reaction mixture is heated atreflux for 16 to 24 hours and then the compounds of formulas If and Igare isolated and purified using standard techniques and procedures, suchas extraction techniques and flash chromatography. For example, thecooled reaction is diluted with a suitable organic solvent, such asethyl acetate, the organic layer is separated, washed with water, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum toprovide the crude oximes. The crude material can then be purified byflash chromatography on silica gel with a suitable eluent, such asmethanol/ethyl acetate to provide the purified compounds of formulas Ifand Ig.

In Scheme VII, step B compounds of formulas If and Ig are reduced understandard conditions to provide the amines of formulas Ih and Ij. Forexample, the compounds of formula If or Ig are dissolved in a suitableorganic solvent, such as diethyl ether and treated with a suitablereducing agent, such as lithium aluminum hydride. The reaction isstirred at a temperature of about room temperature to reflux for about 3to 24 hours. The reaction is then quenched with 1N sodium hydroxide andthe desired compounds of formulas Ih and Ij are isolated and purifedusing standard techniques and procedures. For example, the quenchedreaction mixture is extracted with a suitable organic solvent, such asethyl acetate, the organic extracts are combined, dried over anhydroussodium sulfate, filtered and concentrated under vacuum to provide thecrude material. The crude material is then purified by flashchromatography on silica gel with a suitable eluent, such asmethanol/methylene chloride with ammonia added to provide the purifiedcompounds of formulas Ih and Ij. The free bases are converted to thecorresponding pharmaceutically acceptable salts using standardprocedures well known to one of ordinary skill in the art.

The following examples represent typical syntheses of the compounds offormula I as described generally above. These examples are illustrativeonly and are not intended to limit the invention in any way. Thereagents and starting materials are readily available to one of ordinaryskill in the art. As used herein, the following terms have the meaningsindicated: “eq” refers to equivalents; “g” refers to grams; “mg” refersto milligrams; “L” refers to liters; “mL ” refers to milliliters; “μL”refers to microliters; “mol” refers to moles; “mmol” refers tomillimoles; “psi” refers to pounds per square inch; “min” refers tominutes; “h” refers to hours; “° C.” refers to degrees Celsius; “TLC”refers to thin layer chromatography; “HPLC” refers to high performanceliquid chromatography; “R_(f)” refers to retention factor; “R_(t)”refers to retention time; “δ” refers to part per million down-field fromtetramethylsilane; “THF” refers to tetrahydrofuran; “DMF” refers toN,N-dimethylformamide; “DMSO” refers to methyl sulfoxide; “LDA” refersto lithium diisopropylamide; “aq” refers to aqueous; “iPrOAc” refers toisopropyl acetate; “EtOAc” refers to ethyl acetate; “EtOH” refers toethyl alcohol; “MeOH” refers to methanol; “MTBE” refers to tert-butylmethyl ether; “TMEDA” refers to N,N,N′,N′-tetramethylethylenediamine,and “RT” refers to room temperature.

PREPARATION 1 Preparation of N-Benzyl-3,3-dimethyl-4-piperidone

In a 1 liter 3-necked flask equipped with mechanical stirring, additionfunnel and a calcium chloride drying tube is added a 37% weight solutionof formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absoluteethanol. The resulting solution was cooled in an ice-water bath to 10°C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hourperiod. In a separate 3 liter 3-necked flask equipped with mechanicalstirring, addition funnel and two condensers is added3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 ml of absoluteethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). Theresulting solution is brought to reflux and the formaldehyde/benzylaminesolution is added dropwise over a 2 hour period. This solution isrefluxed overnight, and then cooled to ambient temperature.Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL,0.3 mole) are added and the resulting solution is heated to reflux forsix hours, and then cooled to ambient temperature. The solution wasquenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water,and then extracted with 500 ml ethyl acetate three times. The organicswere concentrated under vacuum to give 225 g of red oil. The crude oilwas dissolved in 1 liter of methylene chloride. This solution wascarefully poured over 1 kg of silica gel on a sintered glass filter. Thesilica gel was washed with 4 L of methylene chloride. The methylenechloride was concentrated under vacuum to provide 142 g of a yellow oilwhich crystallizes in the freezer overnight. Yield=65.4%.

MS(ion spray)=218.3(M+1).

PREPARATION 2 Preparation of1-N-Benzyl-4-hydroxy-4-(2′-(2″,2″-O-diethoxy)ethylthiophenyl)piperidine

A 3 L flask containing 238 mL TMEDA (183.8g, 1.575 mmol) was purged withnitrogen at 5° C. for 10 minutes and n-BuLi (2M in cyclohexane, 786.5mL, 1.537 mole) was added via addition funnel. A mild exotherm and someyellowish precipitate were observed. The addition funnel was rinsedclean with 125 mL of cyclohexane (dried over 4A molecular sieves andpurged with nitrogen). Thiophenol (750 mmol, 82.7 g, 77.30 mL) in 45 mLof cyclohexane was added at such a rate so as to keep the temperaturebelow 22° C., with the aid of an ice bath and vigorous stirring. Thereaction mixture turned clear after 10 mL of the thiophenol solution wasadded, and remained so during the course of the addition which lasted 50minutes. The solution was stirred at room temperature (22° C.) andturned cloudy after 2 h. After stirring for another 20 h at ambienttemperature, the off-white suspension was cooled to −5° C., mixed with500 mL of THF (sieve dried, nitrogen purged), stirred at −5° C. for 20minutes, and then cooled to −60° C. N-benzyl-4-piperidone (distilled,139.86 g, 740 mmol) in 250 mL of THF was added dropwise within 50minutes, while keeping the reaction temperature below −50° C. Theresulting yellow suspension was stirred at −60° C. for 20 minutes, thenallowed to warm to ambient temperature within 2 h to give a clearsolution. Diethyl bromoacetal (149.7 g, 760 mmol) was added, and theresulting solution was heated to reflux at 76° C. for 3 h. Then withcontinuous heating, 1300 mL of solvents were distilled off, while thetemperature reached 100° C. After heating at 100° C. for another 2 h,the solution was cooled to 22° C., mixed with 700 mL of toluene and anequal volume of water (exotherming to 35° C.). The aqueous layer wasextracted with toluene (300 mL×3, and the combined organic layers werewashed with water (300 mL×4) and brine (300 mL×2) to give a toluenesolution of title compound and by-product and residual solvent. The wettoluene solution was dried over anhydrous MgSO₄, vacuum filtered, andconcentrated to afford 345.0 g of crude title compound as an amber oil.The oil was seeded with crystals from previously made title compound,and the flask was cooled in an ice bath. Recrystallization was slow soleaving the mixture standing overnight was necessary. The title compoundcrystallized into a solid mass. Heptane (308 mL) was added to themixture and the solid was broken up with a spatula. The mixture slurrywas cooled in an ice bath with stirring for 3 h, vacuum filtered, washedwith 100 mL of cold (about −22° C.) heptane, and air dried to afford173.93 g (56.555%) of title compound as a beige solid.

PREPARATION 3 Preparation ofN-Benzyl-4-(benzo[b]thiophene-7-yl)-1,2,3,6-tetrahydropyridineHydrochloride

A solution of 1.00 g (0.00241 mol) of1-N-benzyl-4-hydroxy-4-(2′-(2″,2″-O-diethoxy)ethylthio-phenyl)piperidine(prepared in preparation 2) in 20 mL of toluene was added dropwise to 20mL of 6 N HCl (aq) at reflux. Washings with 20 mL of toluene was addedall at once. Water was added after 1 h to replenish the aqueous phase.After heating for 3 h, the mixture was cooled to room temperature andthe title compound, as a white solid, was vacuum filtered, washed with20 mL of THF and air dried to afford 0.18 g (22%) of title compound as awhite solid.

The filtrate was neutralized with 6.00 g of NaHCO₃, 40 mL of 10% NaHCO₃(aq) (pH=8), and extracted with 20 mL of toluene. The organic phase wassaved. The aqueous phase was extracted with a solution of 20 mL of THFand 20 mL of toluene, and then with 20 mL of THF. The organic phaseswere combined, washed with 25 mL of 25% NaCl (aq), dried over anhydrousMgSO₄, gravity filtered, and concentrated to afford 0.69 g of crude freebase of the title compound.

The crude free base of the title compound was purified by gel filtration(silica gel 60; 9:1 hexane: EtOAc) to afford 0.26 g (35%) of free baseof the title compound. Total yield was 57%.

PREPARATION 4 Preparation ofN-Benzyl4-hydroxy-(benzo[b]thiophene-7-yl)-piperidine

A 3-neck 500 mL roundbottom flask fitted with a condenser, droppingfunnel and nitrogen purge, was charged with toluene (600 mL) andmethanesulfonic acid (202 mL, 300 g, 6.5 eq). The mixture was heated to45-55° C., and1-N-benzyl-4-hydroxy-4-(2′-(2″,2″-O-diethoxy)ethylthiophenyl)piperidine(200 g, 481.4 mmol) dissolved in toluene (1400 mL) was added overapproximately 30 minutes maintaining the temperature at 45-50° C. Thereaction mixture was stirred for about 1 to 2 hours at 45-55° C. andthen quenched with a mixture of 2N sodium hydroxide (1685 mL, 7 eq) andisopropyl alcohol (400 mL). The layers were separated and the organicphase was washed with water (1000 mL). Approximately 800 mL of solventwere removed under vacuum (less than 100 mm Hg) and silica G60 (160 g)was added. The mixture was then stirred for at least 30 minutes at roomtemperature. The mixture was then filtered and the silica G60 was rinsedwith toluene (1000 mL). The filtrate was concentrated under vacuum (lessthan 100 mm Hg) to a final pot volume of about 400 mL. The titlecompound could then be isolated by complete concentration under vacuumor, alternatively, it is allowed to remain in the toluene and carried onto the dehydration step.

PREPARATION 5 Alternative Preparation ofN-Benzyl-4-(benzo[b]thiophene-7-yl)-1,2,3,6-tetrahydropyridineHydrochloride

The toluene solution from example 3 containing the compound prepared inpreparation 4 was diluted with isopropyl alcohol (1000 mL) and heated to60° C. Then 2.5 M HCl/isopropanol (212 mL, 1.1 eq) was added over 30minutes. The reaction mixture was then cooled in an ice bath and stirredfor at least one hour at 0° C. The cooled mixture was then filtered, thesolid rinsed with cold isopropyl alcohol and dried under vacuum at 50°C. to provide the title compound (55-60%) as the HCl salt.

PREPARATION 6 Preparation of1-N-Carbethoxy-4-hydroxy-4-(2′-(2″,2″-O-diethoxy)ethylthiophenyl)piperidine

A solution of 2.0M of n-BuLi in cyclohexane (11.99 mL, 24 mmol) wascooled to 5° C. under a nitrogen atmosphere. TMEDA (3.71 mL, 24.6 mmol)was added dropwise keeping the exotherm under 10° C. Thiophenol (1.20mL, 11.7 mmol) in 2 mL cyclohexane was added dropwise keeping theexotherm under 20° C. The resulting solution was allowed to stir toambient temperature overnight. The thick white slurry was cooled to −50°C., and diluted with 2 mL of dry THF. A solution of1-carbethoxy-4-piperidone (2.0 g, 11.7 mmol) in 1 mL of dry THF wasadded dropwise keeping the exotherm less than −50° C. The resultingsolution was warmed to ambient temperature and stirred for 2 hours.Bromo acetaldehyde diethyl acetal (1.78 mL, 11.82 mmol) was added all atonce, and the resulting solution was heated at reflux for 4 hr. Thesolution was cooled to ambient temperature, quenched with pH=7 buffer(50 mL), and extracted with ethyl acetate (3×50 mL). The combinedorganics were absorbed on silica gel, and purified using silica gelflash chromatography to provide the title compound (3.30 g) as acolorless oil.

PREPARATION 7 Preparation of N-Carbethoxy-4-(benzo[b]thiophene-7-yl)-12,3,6-tetrahydropyridine

A solution of methanesulfonic acid (0.98 mL, 15.11 mmol) in 5 mL toluenewas cooled to 0° C. To this solution was added1-N-carbethoxy-4-hydroxy-4-(2′-(2″,2″-O-diethoxy)ethylthio-phenyl)piperidine(1.0 g, 2.52 mmol) in 5 mL of toluene dropwise at 0° C. The solution wasthen stirred at 10° C. for 15 minutes, and slowly warmed to ambienttemperature. After the starting material disappeared by TLC, thereaction was quenched with a saturated solution of sodium bicarbonateand extracted with ethyl acetate (3×25 mL). The organics were dried overanhydrous magnesium sulfate, filtered and purified over silica gel(ethyl acetate/hexane, 1:1) to provide the title compound (123 mg) as alight yellow oil.

PREPARATION 8 Preparation of4-(Benzo[b]thiophene-7-yl)-1,2,3,6-tetrahydropyridine

DissolveN-carbethoxy-4-(benzo[b]thiophene-7-yl)-1,2,3,6-tetrahydropyridine (105mg, 0.3652mmol) in 1 mL ethylene glycol and add potassium hydroxide (102mg, 1.826 mmol) dissolved in 1 mL of water. The reaction mixture isheated at reflux for 8 hours and then cooled to room temperature. It isthen diluted with 5 mL water and extracted with ethyl acetate (3×5 mL),dried over anhydrous magnesium sulfate, filtered and concentrated undervacuum. The reside is purified over silica gel to provide the titlecompound as a yellow oil (51 mg), MS(ion spray)=216.3 (M+1).

EXAMPLE 1 Preparation of4-(7-Benzo(b)thiophene-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-oneOxalate

Preparation of 2-(2-Bromophenylthio)acetaldehyde Diethyl Acetal

Scheme I, step A: A 500 mL round bottom flask was charged with anhydrousDMF (100 mL), 2-bromothiophenol (10.0 g, 52.88 mmol), potassiumcarbonate (11.0 g, 79.59 mmol) and bromoacetaldehyde diethyl acetal(8.35 mL, 55.5 mmol). The reaction was stirred at room temperature for 5hours. Water (50 mL) and ethyl acetate (100 mL) were then added withmixing. The layers were separated and the organic layer was washed withwater (5×50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to provide 2-(2-bromophenylthio)acetaldehydediethyl acetal (13.78 g, 85%).

Preparation of 7-Bromobenzo(b)thiophene

Scheme I, step B: Chlorobenzene (100 mL) and polyphosphoric acid (30.4g, PPA) were combined and heated to reflux. The2-(2-bromophenylthio)acetaldehyde diethyl acetal (13.7 g, 44.88 mmol,Scheme I, step A above) dissolved in chlorobenzene (20 mL) was addeddropwise to the refluxing mixture over 20 minutes. The reaction wasrefluxed for 4 hours and then cooled. The solvent was decanted from theresidue and toluene (2×50 mL) was added to the residue, stirred anddecanted. The toluene extracts were concentrated under vacuum and theresidue taken up in ethyl acetate and water. The organic phase waswashed with saturated sodium bicarbonate, dried over anhydrous sodiumsulfate, filtered and concentrated to provide 7-bromobenzo(b)thiophene(8.91 g, 93%).

Preparation of 1-(t-Butoxycarbonyl)-4-(7-benzo(b)thiophene)-4-hydroxyPiperidine

Scheme I, step C: 7-bromobenzo(b)thiophene (3.01 g, 14.1 mmol, preparedabove in step B) was dissolved in diethyl ether (20 mL) and the solutionwas added dropwise to a suspension of magnesium (0.69 g, 28.3 mmol) indiethyl ether (20 mL). Dibromoethane (1.22 mL, 14.1 mmol) in diethylether (10 mL) was then added dropwise to the reaction mixture, which wasthen heated to reflux for 3 hours. The reaction was then cooled to roomtemperature and 1-(t-butoxycarbonyl)-4-piperidone (2.81 g, 14.1 mmol)was added. The reaction was stirred overnight at room temperature. Waterwas then added to the reaction, and the mixture was extracted withdiethyl ether. The organic layers were combined, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by flash chromatography (hexane:ethyl acetate, 7:3, silica gel)to provide 1-(t-butoxycarbonyl)-4-(7-benzo(b)thiophene-4-hydroxypiperidine (1.14 g).

Preparation of 7-Benzo(b)thiophene-1,2,3,6-tetrahydropyridyl

Scheme I, step D: 1-(t-butoxycarbonyl)-4-(7-benzo(b)thiophene-4-hydroxypiperidine (1.15 g, 3.45 mmol, prepared above in step C) was combinedwith toluene (50 mL) and p-toluenesulfonic acid (1.64 g, 9 8.63 mmol).The mixture was heated to reflux for 2 hours and then cooled. Thereaction mixture was made basic with 1N sodium hydroxide and thenextracted with ethyl acetate. The organic extracts were combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum toprovide 7-benzo(b)thiophene-1,2,3,6-tetrahydropyridyl (0.67 g).

Alternative Preparation of 7-Benzo(b)thiophene-1,2,3,6-tetrahydropyridylPreparation of 1-(t-Butoxycarbonyl)-4-hydroxy-4-tributylstannylPiperidine

Scheme II, step A: Diisopropylamine (25.2 mL, 0.18 mol) in anhydrous THF(500 mL) was cooled to 0° C. and n-butyllithium (112.5 mL of a 1.6 Msolution in THF, 0.18 mol) was added dropwise over 20 minutes to thecooled solution. The reaction mixture was stirred for an additional 15minutes at 0° C. and then tri-n-butyltinhydride (48.4 mL, 0.18 mol) wasadded dropwise over 30 minutes. The reaction mixture was then stirredfor one hour and then cooled to −78° C.N-(t-butoxycarbonyl)-4-piperidone (30.0 g, 0.15 mol) in THF (500 mL) wasthen added dropwise to the cooled solution over one hour. After additionwas complete, the reaction was stirred for 2 hours at −78° C. and thenquenched with buffer (pH 6). The mixture was extracted with ethylacetate, the organic extracts were combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by flash chromatography (5% ethyl acetate/hexane to provide1-(t-butoxycarbonyl)-4-hydroxy4-tributylstannyl piperidine (36.06g).

Preparation of1-(t-Butoxycarbonyl)-4-tributylstannyl-1,2,3,6-tetrahydropyridyl

Scheme II, step B: 1-(t-butoxycarbonyl)-4-hydroxy-4-tributylstannylpiperidine (36.0 g, 73.4 mmol, prepared in Scheme II, step A above) wasdissolved in methylene chloride (250 mL) and cooled to 0° C.Triethylamine (30.7 mL, 220 mmol) and methanesulfonyl chloride (8.56 mL,110 mmol) were added to the solution which was warmed to roomtemperature and allowed to stir for 4 hours. An additional amount ofmethanesulfonyl chloride (4.28 mL) and triethylamine (15.3 mL) was addedand the reaction was allowed to stir for an additional hour at roomtemperature. The reaction mixture was then stored in a freezerovernight. The crude reaction mixture was then concentrated undervacuum. The residue was then purified by flash chromatography (5% ethylacetate/hexane, silica gel) to provide1-(t-Butoxycarbonyl)-4-tributylstannyl-1,2,3,6-tetrahydropyridyl (24.75g, 79%).

Preparation of1-(t-Butoxycarbonyl)-4-(7-benzo(b)thiophene)-1,2,3,6-tetrahydropyridyl

Scheme II, step C: 7-bromobenzo(b)thiophene(0.25 g, 1.17 mmol) and1-(t-butoxycarbonyl)-4-tributylstannyl-1,2,3,6-tetrahydropyridyl (0.55g, 1.17 mmol, prepared in Scheme II, step B above),2,6-di-tert-butyl-4-methylphenol (25 mg) andtetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.04 mmol) werecombined in toluene (10 mL). The reaction mixture was heated to refluxfor 16 hours. It was then cooled, filtered and concentrated to providean orange oil which was purified by flash chromatography (5% ethylacetate/hexane, silica gel) to provide1-(t-butoxycarbonyl)-4-(7-benzo(b)thiophene)-1,2,3,6-tetrahydropyridyl(0.227 g, 61%).

Preparation of 7-Benzo(b)thiophene-1,2,3,6-tetrahydropyridyl

Scheme II, step D:1-(t-butoxycarbonyl)-4-(7-benzo(b)thiophene)-1,2,3,6-tetrahydropyridyl(0.23 g, 0.73 mmol) was combined with p-toluenesulfonic acid in toluene(10 mL) and heated to reflux for one hour. The reaction was cooled toroom temperature and diluted with ethyl acetate (50 mL). The mixture wasthen washed with 1 N sodium hydroxide (3×20 mL), the organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated undervacuum to provide 7-benzo(b)thiophene-1,2,3,6-tetrahydropyridyl(0.14 g,96%).

Preparation of 1-Cyclohexyl-2-(2-pyridyl)ethan-1-one

Scheme III, step A: A 100 mL round bottom flash was charged with2-picoline (1.09 mL, 11.02 mmol) and anhydrous THF (15 mL). The solutionwas cooled to −78° C. and n-butyllithium (7.6 mL of a 1.6M solution inTHF, 12.12 mmol) was added dropwise to the cooled solution. Afteraddition was complete, the reaction mixture was warmed to roomtemperature over one hour and then cooled again to −78° C.N-methoxy-N-methyl cyclohexyl amide (2.0 g, 11.68 mmol) in THF (10 mL)was added dropwise to the reaction mixture. After addition was complete,the reaction was warmed to room temperature over one hour and thenstirred for 40 hours. The reaction mixture was then treated with waterand 1N HCl (keeping the pH at approximately 12). The reaction mixturewas then extracted with methylene chloride (3×20 mL). The organicextracts were combined, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum to provide an orange oil which waspurified by flash chromatography (ethyl acetate:hexane, 3:7, silica gel)to provide 1-cyclohexyl-2-(2-pyridyl)ethan-1-one (2.06 g).

Preparation of1-Cyclohexyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one

Scheme III, step B: A 250 mL round bottom flask was charged withanhydrous DMF (30 mL) and sodium hydride (0.56 g of a 60% dispersion,14.0 mmol). The suspension was cooled to 0° C. and1-cyclohexyl-2-(2-pyridyl)ethan-1-one (2.03 g, 10 mmol) in THF (30 mL)was added dropwise to the suspension. After addition was complete, thereaction was stirred for 2.5 hours at room temperature. Then2-bromomethyl-1,3-dioxolane (1.55 mL, 15 mmol) was added and thereaction was heated at reflux for 16 hours. The reaction mixture wasthen quenched with water and extracted with diethyl ether (4×50 mL). Thecombined organic extracts were dried over anhydrous magnesium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate:hexane, 3:7, silica gel) to provide1-cyclohexyl-3-(2-(1,2-dioxolane))-2-(2-pyridyl)propan-1-one (1.79 g,62%) as a yellow oil.

Preparation of 1-Cyclohexyl-2-(2-pyridyl)butan-1-one-4-al

Scheme III, step C:1-cyclohexyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one (0.40 g,1.38 mmol, prepared above) was dissolved in acetone (10 mL), treatedwith 3N HCl (10 mL) and stirred for 16 hours at room temperature. Thereaction mixture was basified with 1N sodium hydroxide (pH=8-9) andextracted with ethyl acetate. The organic extracts were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toprovide crude 1-cyclohexyl-2-(2-pyridyl)butan-1-one-4-al which wascarried on to the next step without further purification.

Preparation of the Final Title Compound

Scheme IV, step A: 1-cyclohexyl-2-(2-pyridyl)butan-1-one-4-al(approximately 1.38 g, prepared in Scheme III, step C above) is combinedwith 7-benzo(b)thiophene-1,2,3,6-tetrahydropyridyl (0.14 g, 9 0.65 mmol,prepared in Scheme I, step D or Scheme II, step D above) in methylenechloride (20 mL) with acetic acid (0.11 mL, 1.95 mmol) and sodiumtriacetoxyborohydride (0.37 g, 1.76 mmol). The reaction mixture wasstirred at room temperature for 18 hours. It was then treated with 1Nsodium hydroxide and extracted with methylene chloride. The combinedorganic extracts were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by flashchromatography sodium sulfate, filtered and concentrated under vacuum.The residue was purified by flash chromatography (1:1 hexane:ethylacetate, silica gel) to provide the free base of the title compound(0.237 g, 82%).

This free base was treated with oxalic acid (41.6 mg) in methanol. Theresulting crystals were then collect by filtration to provide the titlecompound (0.206 g) mp 120-122° C.

Preparation of4-(7-Benzo(b)thiophene-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-oneHCl

To the free base,4-(7-benzo(b)thiophene-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-one(14.99 g, 33.7 mmole, prepared above) was added acetone (210 mL) andmethyl t-butyl ether (150 mL). The solution was heated to reflux and1.64 N anhydrous HCl in methyl t-butyl ether (20.5 mL) was added slowlywhile keeping the product in solution. After all of the HCl solution wasadded, additional methyl t-butyl ether (20 mL) was added and thesolution was allowed to cool to room temperature gradually. After thesolution was stirred at room temperature for a few hours, the solutionwas filtered under a positive pressure of nitrogen. The white solid wasdried at 50° C. in vacuo to afford 11.68 g (72%) of the title compound.mp=147-154° C., ¹H NMR (CDCl₃) δ 8.54 (dd, J=4.9, 0.9 Hz, 1H), 7.76 (dd,J=7.9, 0.9 Hz, 1H), 7.71 (dt, J=7.7, 1.9 Hz, 1H), 7.44 (d, J=5.5 Hz,1H), 7.42 (d, J=7.9 Hz, 1H), 7.40-7.34 (m, 2H), 7.22 (d, J=7.6 Hz, 1H),7.21 (dd, J=7.6, 0.9 Hz, 1H), 6.17 (s, 1H), 4.33 (dd, J=7.6, 6.1, 1H),4.20-3.62 (br m, 1H), 3.62-3.24 (br m, 2H), 3.24-3.04 (m, 2H), 3.04-2.75(br m, 1H), 2.75-2.59 (m, 1H), 2.55-2.29 (m, 2H), 1.96-1.50 (m, 5H),1.50-0.97 (m, 7H).

Preparation of4-(7-Benzo(b)thiophene-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-one2HCl

4-(7-benzo(b)thiophene-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-one(1 equivalent, free base prepared above) was dissolved in methanol. HClin ether (2 equivalents) was then added. After it was stirred at roomtemperature for 5 minutes, the volatile was evaporated. The whiteprecipitate was dried under vacuum for 12 hours to provide the titlecompound, which slowly absorbs water from air. The melting point variesdepending upon the amount of water absorbed: 118-130° C.

EXAMPLE 2 Preparation of4-(7-Benzo(b)thiophene-1,2,3,6-tetrahydropyridyl)-1-cycloheptyl-2-(2-pyridyl)butan-1-oneOxalate

Preparation of N-methoxy-N-methyl Cycloheptyl Amide

Cycloheptanecarboxylic acid (25.0 g, 0.176 mol) was dissolved inmethylene chloride (100 mL) and oxalyl chloride (23 mL, 0.264 mol) wasadded dropwise to the solution. The reaction mixture was stirred for 30minutes at room temperature and then concentrated under vacuum toprovide the acid chloride of cycloheptanecarboxylic acid as a yellowoil.

N,O-dimethylhydroxylamine hydrochloride (18.03 g, 0.185 mol) wassuspended in methylene chloride (200 mL) and treated with triethylamine(49.1 mL, 0.35 mol). The mixture was stirred for 15 minutes at roomtemperature and then cooled to 0° C. The above-formed acid chloride ofcycloheptanecarboxylic acid dissolved in methylene chloride (30 mL) wasadded dropwise to the cooled solution. After addition was complete, thereaction mixture was warmed to room temperature and allowed to stir for17 hours. The mixture was then poured into water (200 mL). The layerswere separated, and the organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated to provide N-methoxy-N-methylcycloheptyl amide.

Preparation of 1-Cycloheptyl-2-(2-pyridyl)ethan-1-one

Scheme III, step A: A 100 mL round bottom flask was charged with2-picoline (2.52 mL, 25.5 mmol) and anhydrous THF (30 mL). The solutionwas cooled to −78° C. and n-butyllithium (17.5 mL of a 1.6 M solution inTHF, 28.05 mmol) was added dropwise to the solution. After addition wascomplete, the reaction was warmed slowly to room temperature over onehour and then cooled again to −78° C. N-methoxy-N-methyl cycloheptylamide (5.0 g, 27.03 mmol, formed above) was added to the reaction. Thereaction mixture was allowed to warm to room temperature with stirringovernight. The reaction was carefully quenched with water and extractedwith ethyl acetate. The organic extracts were dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by flash chromatography (ethyl acetate:hexane, 3:7, silica gel)to provide 1-cycloheptyl-2-(2-pyridyl)ethan-1-one (5.03 g, 91%)

Preparation of1-Cycloheptyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one

Scheme III, step B: 1-cycloheptyl-2-(2-pyridyl)ethan-1-one (5.0 g, 23.0mmol, prepared above in Scheme III, step A) was dissolved in anhydrousTHF (50 mL) was added dropwise to a suspension of sodium hydride (1.29 gof a 60% dispersion, 32.2 mmol) in anhydrous DMF cooled to 0° C. Thereaction mixture was then warmed to room temperature and stirred for onehour. Then 2-bromomethyl-1,3-dioxolane (3.58 mL, 34.5 mmol) andpotassium iodide (0.5 g, crushed) were added and the reaction mixturewas heated at reflux for 16 hours. Water was added, and the mixture wasextracted with ethyl acetate. The organic extracts were combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by flash chromatography (ethyl acetate/hexane,3/7, silica gel) to provide1-cycloheptyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one (4.52 g,65%).

Preparation of 1-Cycloheptyl-2-(2-pyridyl)butan-1-one-4-al

Scheme III, step C;1-cycloheptyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one (0.51 g,1.68 mmol) was dissolved in acetone (10 mL), treated with 3N HCl (10 mL)and stirred for 16 hours at room temperature. The reaction mixture wasneutralized with 1N sodium hydroxide (30 mL) and extracted with ethylacetate. The organic extracts were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to provide1-cycloheptyl-2-(2-pyridyl)butan-1-one-4-al.

Preparation of Final Title Compound

Scheme IV, step A: 1-cycloheptyl-2-(2-pyridyl)butan-1-one-4-al (0.31 g,1.19 mmol, prepared in Scheme III, step C above) is combined with7-benzo(b)thiophene-3,4-dehydropiperidine (0.26 g, 1.19 mmol, preparedin Example 1, Scheme I, step D) in methylene chloride (10 mL) withacetic acid (0.17 mL, 2.98 mmol) and sodium triacetoxyborohydride (0.33g, 1.55 mmol). The reaction mixture was stirred at room temperature for5 hours. It was then made basic with 1N sodium hydroxide and extractedwith methylene chloride. The combined organic extracts were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by flash chromatography (ethyl acetate:hexane, 1:1,silica gel) to provide the free base of the final title compound (0.19g).

This free base was treated with oxalic acid (37.6 mg) in methanol. Theresulting crystals were filtered to provide the final title compound(0.206 g) mp 105-108° C.

EXAMPLE 3 Preparation of4-(7-Benzo(b)thiophene-1,2,3,6-tetrahydropyridyl)-1-cyclopentyl-2-(2-pyridyl)butan-1-oneOxalate

Preparation of 1-Cyclopentyl-2-(2-pyridyl)ethan-1-one

Scheme III, step A: A 100 mL round bottom flask was charged with2-picoline (2.97 mL, 30.05 mmol) and anhydrous THF (30 mL). The solutionwas cooled to −78° C. and n-butyllithium (20.7 mL of a 1.6 M solution inTHF, 33.1 mmol) was added dropwise. The reaction mixture was slowlywarmed to room temperature and then stirred for one hour. The reactionmixture was then cooled back to −78° C. andN-methoxy-N-methyl-cyclopentyl amide (5.0 g, 31.85 mmol) was added. Thereaction mixture was allowed to warm to room temperature overnight withstirring and then quenched with 0.1 N HCl to pH 9. The mixture was thenextracted with methylene chloride, the organic extracts were combined,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by flash chromatography (ethylacetate:hexane, 3:7, silica gel) to provide1-cyclopentyl-2-(2-pyridyl)ethan-1-one (4.35 g, 77%).

Preparation of1-Cyclopentyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one

Scheme III, step B: A 500 round bottom flask was charged with 60% sodiumhydride (1.27 g, 31.9 mmol) and anhydrous DMF (50 mL). The suspensionwas cooled to 0° C. and 1-cyclopentyl-2-(2-pyridyl)ethan-1-one (4.30 g,22.8 mmol, prepared above in Scheme III, step A) dissolved in anhydrousTHF (50 mL) was added dropwise to the suspension. The reaction mixturewas warmed to room temperature and stirred for one hour. Then2-bromomethyl-1,3-dioxolane (3.54 mL, 34.2 mmol) and potassium iodide(0.2 g, crushed) were added and the reaction mixture was heated atreflux for 6 hours. The reaction mixture was then cooled to roomtemperature and stirred for 16 hours. Water was added, and the mixturewas extracted with ethyl acetate. The organic extracts were combined,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by flash chromatography (ethylacetate:hexane, 3:7, silica gel) to provide1-cyclopentyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one (1.43 g).

Preparation of 1-Cyclopentyl-2-(2-pyridyl)butan-1-one-4-al

Scheme III, step C:1-cyclopentyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one (0.48 g,1.75 mmol, prepared above in Scheme III, step B) was combined with 3NHCl (10 mL) and acetone (10 mL), and the reaction mixture was stirredovernight at room temperature. The reaction mixture was then neutralizedwith 1N sodium hydroxide (30 mL) and extracted with diethyl ether. Theorganic extracts were combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to provide1-cyclopentyl-2-(2-pyridyl)butan-1-one-4-al (0.165 g).

Preparation of Final Title Compound

Scheme IV, step A: 1-cyclopentyl-2-(2-pyridyl)butan-1-one-4-al (0.38 g,1.64 mmol, prepared in Scheme III, step C above) was combined with7-benzo(b)thiophene-3,4-dehydropiperidine (0.35 g, 1.64 mmol, preparedin Example 1, Scheme I, step D) in methylene chloride (20 mL) withacetic acid (0.23 mL, 4.1 mmol) and sodium triacetoxyborohydride (0.45g, 2.1 mmol). The reaction mixture was stirred at room temperature for16 hours. It was then made basic with 1N sodium hydroxide and extractedwith methylene chloride (20 mL). The organic extract was dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by flash chromatography (ethyl acetate:hexane, 6:4,silica gel) to provide the free base of the final title compound (0.28g, 39%).

The above free base was treated with oxalic acid (56.8 mg) in methanol.The resulting crystals were filtered to provide the oxalate salt of thefinal title compound (0.28 g) mp 118-120° C.

EXAMPLE 4 Preparation of4-(7-Benzo(b)thiophene-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-oneOxalate

Preparation of 7-Benzo(b)thiophene-piperidine

Scheme I, step E: 7-benzo(b)thiophene-3,4-dehydropiperidine (0.75 g, 3.5mmol, prepared in Example 1, Scheme I, step D) was dissolved in ethanol(25 mL). 10% Palladium on carbon (2.25 g) was added and the reaction wasstirred under hydrogen at 60 psi at room temperature overnight. Thereaction mixture was filtered and the filtrate concentrated to provide7-benzo(b)thiophene-piperidine.

Preparation of Final Title Compound

Scheme IV, step A; 1-cyclohexyl-2-(2-pyridyl)butan-1-one-4-al (0.20 g,0.83 mmol, prepared in Example 1, Scheme III, step C) is combined with7-benzo(b)thiophene-piperidine (0.13 g, 0.60 mmol, prepared in Scheme I,step E above) in methylene chloride (10 mL) with acetic acid (0.09 mL,1.5 mmol) and sodium triacetoxyborohydride (0.17 g, 0.78 mmol). Thereaction mixture was stirred at room temperature overnight. It was thenmade basic with 1N sodium hydroxide and extracted with methylenechloride. The organic extract was dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified byflash chromatography (2% methanol/ethyl acetate, silica gel) to providethe free base of the final title compound (0.168 g, 62%).

The free base was then treated with oxalic acid (34 mg) in methanol. Theresulting crystals were filtered to provide the final title compound(0.13 g) mp 122-125° C.

EXAMPLE 5 Preparation of4-(7-Benzo(b)furan-3,4-dehydropiperidinyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-oneDihydrochloride

Preparation of 2-(2-Bromophenol)acetaldehyde Diethyl Acetal

Scheme I, step A: 2-Bromophenol (22.65 g, 0.13 mol) was dissolved inanhydrous DMF (10 mL) and added over 15 minutes to a suspension ofsodium hydride (5.76 g of a 60% dispersion, 0.14 mol) in anhydrous DMF(90 mL) at 0° C. The reaction was stirred for an additional 15 minutesand bromoacetaldehyde diethyl acetal (38.4 g, 0.195 mol) was added. Thereaction was then heated at reflux for 2 hours. The reaction mixture wasthen poured into water (100 mL) and extracted with ethyl acetate (3×200mL). The organic extracts were combined, washed with water (5×100 mL),dried over anhydrous sodium sulfate, filtered and concentrated undervacuum to provide a yellow oil. This oil was then purified by flashchromatography (hexane:ethyl acetate, 9:1, silica gel) to provide2-(2-bromophenol)acetaldehyde diethyl acetal as a yellow oil.

Preparation of 7-Bromobenzo(b)furan.

Scheme I, step B: Polyphosphoric acid (60 g) and chlorobenzene (100 mL)were combined and heated to reflux. To the refluxing mixture was addeddropwise 2-(2-bromophenol)acetaldehyde diethyl acetal (27 g, 0.093 mol,prepared above in Scheme I, step A) dissolved in chlorobenzene (20 mL)over 15 minutes. Heating of the reaction mixture at reflux was continuedfor 2 hours and then it was cooled to room temperature. 1N sodiumhydroxide (100 mL) was added and the reaction was stirred at roomtemperature overnight. The reaction mixture was then extracted withdiethyl ether (3×100 mL), the organic extracts were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by flash chromatography (hexane, silica gel) toprovide the 7-bromobenzo(b)furan (13.4 g, 73%) as a clear oil.

Preparation of 1-(t-Butoxycarbonyl)-4-(7-benzo(b)furan)-4-hydroxyPiperidine

Scheme I, step C: A 500 mL round bottom flask was charged with anhydrousTHF (150 mL) and 7-bromobenzo(b)furan (13.0 g, 0.066 mol, prepared abovein Scheme I, step B), and the solution was cooled to −78° C.n-Butyllithium (41.2 mL of a 1.6 M solution in THF, 0.066 mol) was addedover 3 minutes followed by addition of 1-(t-butoxycarbonyl)-4-piperidone(12.52 g, 0.063 mol). The reaction mixture was then allowed to warm toroom temperature over 18 hours with stirring. The reaction was thenquenched with water (4 mL) and extracted with ethyl acetate. The organicextracts were combined, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum to provide a tan oil. The tan oil was thenpurified by flash chromatography (silica gel, 2 times) to provide1-(t-butoxycarbonyl)-4-(7-benzo(b)furan)-4-hydroxy piperidine (0.2 g).

Preparation of 7-Benzo(b)furan-1,2,3,6-tetrahydropyridyl

Scheme I, step D: A 500 mL round bottom flask was charged with1-(t-butoxycarbonyl)-4-(7-benzo(b)furan)-4-hydroxy piperidine (13.1 g,0.041 mol, prepared above in Scheme I, step C), p-toluenesulfonic acid(19.63 g, 0.10 mol) and toluene (100 mL). The reaction mixture was thenheated at reflux for 3 hours during which 2.7 mL of water was collectedin a Dean-Stark trap. The reaction mixture was then cooled to roomtemperature and concentrated under vacuum to a brown oil. Saturatedpotassium carbonate solution was added to basify and the mixture wasextracted with ethyl acetate (2×100 mL). The organic extracts werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by flash chromatography(methanol:ammonium hydroxide:methylene chloride, 20:2:78, silica gel) toprovide 7-benzo(b)furan-1,2,3,6-tetrahydropyridyl (1.6 g).

Preparation of Final Title Compound

Scheme IV, step A: 1-cyclohexyl-2-(2-pyridyl)butan-1-one-4-al (0.40 g,1.63 mmol, prepared in Example 1, Scheme III, step C) was combined with7-benzo(b)furan-1,2,3,6-tetrahydropyridyl (0.33 g, 1.63 mmol, preparedin Scheme I, step D above) in methylene chloride (20 mL) with aceticacid (0.20 mL, 3.42 mmol) and sodium triacetoxyborohydride (0.45 g, 2.12mmol). The reaction mixture was stirred at room temperature for 2.5hours. It was then made basic with 1N sodium hydroxide and extractedwith methylene chloride (2×50 mL). The organic extracts were combined,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by chromatography (ethyl acetate,silica gel) to provide a yellow oil. The oil was taken up in diethylether which was then treated with 1 N HCl in diethyl ether. A whiteprecipitate formed which was collected by filtration and dried toprovide the title compound (0.23 g) mp 150-154° C.

EXAMPLE 6 Preparation of4-(7-Benzo(b)furan-1,2,3,6-tetrahydropyridyl)-1-phenyl-2-phenyl-butan-1-oneOxalate

Preparation of 1-Phenyl-3-(2-(1,3-dioxolane))-2-phenyl-propan-1-one

Scheme III, step B: To a stirred lithium diisopropyl amide solution (6.2mmol in 10 mL of THF)was added deoxybenzoin (1.10 g, 9 5.6 mmol) in DMF(10 mL) at 0° C. under an atmosphere of nitrogen. The mixture wasstirred at room temperature for 2 hours and then heated to reflux for 12hours. The title compound was isolated by standard work-up and purifiedby purified by flash chromatography to provide 1.17 g (74%).

Preparation of 1-Phenyl-2-phenyl-butan-1-one-4-al

Scheme III, step C: A 500 mL round bottom flask was charged with1-phenyl-3-(2-(1,3-dioxolane))-2-phenyl-propan-1-one (2.50 g, 8.85 mmol,prepared above in Scheme III, step B above), acetone (100 mL) and 2N HCl(100 mL). The reaction was then stirred at room temperature for 6 hoursand then made slightly basic (pH 10) with 1N NaOH. The reaction was thenpartially concentrated under vacuum and the aqueous/residue wasextracted with diethyl ether (2×100 mL). The organic extracts werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to provide 1-phenyl-2-phenyl-butan-1-one-4-al.

Preparation of Final Title Compound

Scheme IV, step A: 1-phenyl-2-phenyl-butan-1-one-4-al (0.50 g, 2.1 mmol,prepared above in Scheme III, step C), acetic acid (0.25 mL, 4.2 mmol),methylene chloride (20 mL) and 7-benzo(b)furan-3,4-dehydropiperidine(0.42 g, 2.1 mmol, prepared in Example 5, Scheme I, step D) werecombined with sodium triacetoxyborohydride (0.58 g, 2.7 mmol) andstirred at room temperature for 16 hours. The reaction was then treatedwith 1 N sodium hydroxide (5 mL) and extracted with methylene chloride.The organic extracts were combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified byflash chromatography to provide the free base of the title compound(0.533 g).

The free base was treated with oxalic acid (114 mg) in methanol. Thesolution was concentrated to provide the final title compound (0.48 g)as a yellow powder, mp 85-87° C.

EXAMPLE 7 Preparation of4-(7-Benzo(b)furan-1,2,3,6-tetrahydropyridyl)-1-cyclopentyl-2-(2-pyridyl)butan-1-oneOxalate

Scheme IV, step A: 1-cyclopentyl-2-(2-pyridyl)butan-1-one-4-al (0.16 g,0.69 mmol, prepared in Example 3, Scheme III, step C),7-benzo(b)furan-1,2,3,6-tetrahydropyridyl (0.15 g, 0.76 mmol, preparedin Example 5, Scheme I, step D), methylene chloride (10 mL), and aceticacid (0.08 mL, 1.39 mmol) were combined and treated with sodiumtriacetoxyborohydride (0.19 g, 0.90 mmol). The reaction mixture wasstirred at room temperature for 3 hours and then made basic with 1Nsodium hydroxide (5 mL). The reaction mixture was then extracted withmethylene chloride, the organic extracts were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by flash chromatography (ethyl acetate, silica gel)to provide the free base of the title compound (0.13 g, 45%).

The free base was dissolved in methanol and treated with oxalic acid (28mg) and concentrated under vacuum to provide the final title compound(0.15 g) mp 160-163° C.

EXAMPLE 8 Preparation of4-(7-Benzo(b)furan-1,2,3,6-tetrahydropyridyl)-1-cycloheptyl-2-(2-pyridyl)butan-1-oneOxalate

Scheme IV, step A: 1-Cycloheptyl-2-(2-pyridyl)butan-1-one-4-al (0.50 g,1.93 mmol, prepared in Example 2, Scheme III, step C)),7-benzo(b)furan-1,2,3,6-tetrahydropyridyl (0.42 g, 2.12 mmol, preparedin Example 5, Scheme I, step D), methylene chloride (20 mL), and aceticacid (0.28 mL, 4.83 mmol) were combined and treated with sodiumtriacetoxyborohydride (0.53 g, 2.51 mmol). The reaction mixture wasstirred at room temperature for 3.5 hours and then made basic with 1Nsodium hydroxide (5 mL). The reaction mixture was then extracted withmethylene chloride, the organic extracts were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by flash chromatography (ethyl acetate, silica gel)to provide the free base of the final title compound (0.53 g, 62%).

The free base was dissolved in methanol and treated with oxalic acid(0.104 g) and concentrated under vacuum to provide the final titlecompound (0.420 g) mp 118-119° C.

EXAMPLE 9 Preparation of4-(5-Fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-oneOxalate

Preparation of 2-(2-Bromo-4-fluorophenol)acetaldehyde Diethyl Acetal

Scheme I, step A: A 500 mL round bottom flask was charged with sodiumhydride (8.69 g of a 60% dispersion, 0.217 mol) and anhydrous DMF (130mL), and the suspension was cooled to 0° C. To the cooled stirringsuspension was added 2-bromo-4-fluorophenol (39.5 g, 0.207 mmol)dissolved in anhydrous DMF (20 mL). The reaction was stirred for 30minutes after addition and then bromoacetaldehyde diethyl acetal (42.8g, 0.217 mol) was added. The reaction was then heated at reflux for 2.5hours, cooled to room temperature, and stirred for 24 hours. Thereaction mixture was then poured into water and extracted with ethylacetate (2×200 mL). The organic extracts were combined, washed withwater (5×100 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by flashchromatography to provide 2-(2-bromo-4-fluorophenol)acetaldehyde diethylacetal (53.3 g).

Preparation of 5-Fluoro-7-bromo-benzo(b)furan

Scheme I, step B: A 500 mL round bottom flask was charged withchlorobenzene (120 mL) and polyphosphoric acid (40.0 g), and the mixturewas heated to reflux. To the refluxing mixture was added dropwise2-(2-bromo-fluorophenol)acetaldehyde diethyl acetal (48.3 g, 0.16 mol,prepared in Scheme I, step A above) dissolved in chorobenzene (60 mL).After refluxing for 2 hours at room temperature, the reaction mixturewas cooled to room temperature and poured into 1 N sodium hydroxide. Thereaction mixture was then stirred for 16 hours, extracted with diethylether, the organic extracts were combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by flash chromatography (hexane, silica gel) to provide5-fluoro-7-bromo-benzo(b)furan (9.3 g) as a clear oil.

Preparation of1-(t-Butoxycarbonyl)-4-(5-fluoro-7-benzo(b)furan-4-hydroxy Piperidine

Scheme I, step C: A 200 mL round bottom flask was charged with anhydrousTHF (100 mL), 5-fluoro-7-bromo-benzo(b)furan (2.2 g, 0.01 mol) and1-(t-butoxycarbonyl)-4-piperidone (2.2 g, 0.011 mol). The solution wascooled to −78° C. and treated with sec-butyllithium (8.3 mL of a 1.3 Msolution in cyclohexane, 0.011 mol). The reaction mixture was thenslowly warmed to room temperature and stirred for 16 hours. The reactionmixture was then quenched with water and extracted with ethyl acetate(2×100 mL). The organic extracts were combined, dried over anhydroussodium sulfate, filtered and concentrated under vacuum to provide ayellow solid. This yellow solid was recrystallized from diethyl ether toprovide 1-(t-butoxycarbonyl)-4-(5-fluoro-7-benzo(b)furan)-4-hydroxypiperidine (0.45 g, 13.4% as a tan solid, mp 228-230° C.

Preparation of 5-Fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl

Scheme I, step D:1-(t-butoxycarbonyl)-4-(5-fluoro-7-benzo(b)furan)-4-hydroxy piperidine(4.16 g, 12.42 mmol, prepared in Scheme I, step C above) was dissolvedin toluene (120 mL) and treated with p-toluenesulfonic acid (5.91 g,31.04 mmol). The reaction mixture was heated to reflux for 3 hours, thencooled to room temperature and then made basic with 1 N sodiumhydroxide. The layers were separated, the organic phase was dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was taken up in ethyl acetate, washed with 1N sodium hydroxide(3×50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to provide5-fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl.

Alternative Route:

Preparation of1-(t-Butoxycarbonyl)-4-(5-fluoro-7-benzo(b)furan)-1,2,3,6-tetrahydropyridyl

Scheme II, step C: 5-fluoro-7-bromo-benzo(b)furan (5.40 g, 25.13 mmol,prepared in Scheme I, step B above) was combined with1-(t-butoxycarbonyl)-4-tributylstannyl-1,2,3,6-tetrahydropyridyl (11.87g, 25.13 mmol, prepared in Example 1, Scheme II, step B ), toluene (150mL) and tetrakis(triphenylphosphine)palladium(0) (0.99 g, 0.85 mmol).The reaction mixture was heated to reflux for 20 hours, then cooled toroom temperature and quenched with water. The reaction was thenextracted with ethyl acetate, the organic extracts were combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by flash chromatography (hexane:ethyl acetate,9:1, silica gel) to provide1-(t-butoxycarbonyl)-4-(5-fluoro-7-benzo(b)furan)-1,2,3,6-tetrahydropyridyl(6.47 g, 81%).

Preparation of 5-Fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl

Scheme II, step D:1-(t-butoxycarbonyl)-4-(5-fluoro-7-benzo(b)furan)-1,2,3,6-tetrahydropyridyl(6.47 g, 20.4 mmol, prepared above in Scheme II, step C) was combinedwith p-toluenesulfonic acid (11.65 g, 61.2 mmol) and toluene (200 mL).The reaction mixture was heated at reflux for 1.5 hours. It was thendiluted with ethyl acetate (300 mL) and washed with 1N sodium hydroxide(3×200 mL). The organic phase was dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was taken up in 0.2NHCl, the aqueous was washed with diethyl ether (3×200 mL) and then theaqueous was made basic with 5N sodium hydroxide. The aqueous was thenextracted with diethyl ether, the organic extracts were combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum toprovide 5-fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl (3.15 g,71%).

Preparation of 1-Cyclohexyl-2-(2-pyridyl)butan-1-one-4-al

Scheme III, step C:1-cyclohexyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one (0.50 g,1.73 mmol, prepared in Example 1, Scheme III, step B) was combined withacetone (10 mL) and 3N HCl (10 mL). The reaction mixture was stirred for18 hours at room temperature and then neutralized with 1N sodiumhydroxide (30 mL). The neutralized mixture was then extracted withdiethyl ether, the organic extracts were combined, dried over anhydroussodium sulfate, filtered and concentrated under vacuum to provide1-cyclohexyl-2-(2-pyridyl)butan-1-one-4-al (0.22 g).

Preparation of Final Title Compound

Scheme IV, step A: 1-cyclohexyl-2-(2-pyridyl)butan-1-one-4-al (0.22 g,prepared in Scheme III, step C above),5-fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl (0.20 g, 0.90 mmol,prepared in Scheme I, step D or Scheme II, step D above), methylenechloride (10 mL), and acetic acid (0.15 mL, 2.7 mmol) were combined andtreated with sodium triacetoxyborohydride (0.25 g, 1.17 mmol). Thereaction mixture was stirred at room temperature for 3 hours and thenmade basic with 1N sodium hydroxide (5 mL). The reaction mixture wasthen extracted with methylene chloride, the organic extracts werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by flash chromatography toprovide the free base of the final title compound (0.19 g, 47%).

The free base was dissolved in methanol and treated with oxalic acid(38.3 mg) and concentrated under vacuum to provide the final titlecompound (0.188 g) mp 117-120° C.

EXAMPLE 10 Preparation of4-(2-Methyl-5-fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-oneOxalate

Preparation of Ethyl 2-(2′-Bromo-4′-fluorophenoxy)propionate

Scheme IA, step A: 2-bromo-4-fluorophenol (15.0 g, 78.5 mmol) wasdissolved in THF (200 mL) and treated with potassium carbonate (13.0 g,94.2 mmol) and ethyl 2-bromopropionate (11.2 mL, 86.4 mmol). Thereaction mixture was heated at reflux for 3 hours. Potassium iodide (0.1g) was added and the reaction mixture was stirred for an additional 2hours at reflux. The reaction was then cooled, diluted with water andextracted with ethyl acetate. The organic extracts were combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by flash chromatography to provide ethyl2-(2′-bromo-4′-fluorophenoxy)propionate (19.8 g) as a clear oil.

Preparation of 2-(2′-Bromo-4′-fluoro)phenoxypropionaldehyde.

Scheme IA, step B: ethyl 2-(2′-bromo-4′-fluorophenoxy)propionate (19.4g, 66.7 mmol, prepared in Scheme IA, step A above) was dissolved inanhydrous toluene (400 mL) and cooled to −78° C. The cooled solution wasthen treated dropwise over 35 minutes with diisobutylaluminum hydride(100 mL of a 1M solution in toluene, 100 mmol). It was then stirred foran additional 20 minutes and then quenched at −78° C. with methanol.After warming to room temperature it was diluted with saturated sodiumtartrate solution for 30 minutes and then extracted with ethyl acetate.The organic extracts were combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to provide2-(2′-bromo-4′-fluoro)phenoxypropionaldehyde (16.9 g).

Preparation of 2-Methyl-5-fluoro-7-bromo-benzo(b)furan

Scheme IA, step C: 2-(2′-Bromo4′-fluoro)phenoxypropionaldehyde (16.5 g,66.8 mmol, prepared above in Scheme IA, step B) was dissolved inchlorobenzene (100 mL) and added dropwise to a refluxing mixture ofpolyphosphoric acid (60 g) in chlorobenzene (300 mL). After addition wascomplete, the reaction mixture was heated at reflux for 3 hours and thencooled to room temperature overnight. The reaction mixture was thenslowly poured into dilute sodium hydroxide and stirred for 30 minutes.The mixture was extracted with ethyl acetate (3×300 mL), the organicextracts were combined, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The black residue was purified by flashchromatography (hexane, silica gel) to provide2-methyl-5-fluro-7-bromo-benzo(b)furan (5.2 g).

Preparation of1-(t-Butoxycarbonyl)-4-(2-methyl-5-fluoro-7-benzo(b)furan)-4-hydroxyPiperidine

Scheme I, step C: 2-methyl-5-fluro-7-bromo-benzo(b)furan (3.70 g, 16.16mmol, prepared above in Scheme IA, step C) was dissolved in anhydrousTHF (100 mL), the solution was cooled to −78° C. and then treated withn-butyllithium (11.12 mL of a 1.6 M solution in THF, 17.74 mmol). Afteraddition was complete, the reaction was stirred for an additional 10minutes at −78° C. and 1-(t-butoxycarbonyl)-4-piperidone (3.54 g, 17.78mmol) was added. The reaction mixture was allowed to warm to roomtemperature overnight and then it was quenched with water. The quenchedreaction was then extracted with ethyl acetate, the combined organicextracts were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by flashchromatography to provide1-(t-butoxycarbonyl)-4-(2-methyl-5-fluoro-7-benzo(b)furan)-4-hydroxypiperidine (3.68 g, 65%).

Preparation of2-Methyl-5-fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl Oxalate

Scheme I, step D:1-(t-butoxycarbonyl)-4-(2-methyl-5-fluoro-7-benzo(b)furan-4-hydroxypiperidine (3.68 g, 10.54 mmol, prepared above in Scheme I, step C) wasdissolved in toluene (50 mL) and treated with p-toluenesulfonic acid(8.02 g, 42.18 mmol). The reaction was heated at reflux for 1.5 hours,then cooled to room temperature and concentrated under vacuum to ayellow semi-solid. The semi-solid was suspended in ethyl acetate andwashed with 1N sodium hydroxide (5×50 mL). The organic phase was thendried over anhydrous sodium sulfate, filtered and concentrated undervacuum to provide the free base of the title compound as a yellow oil.The oil was dissolved in methanol, treated with oxalic acid (0.77 g) andthen concentrated under vacuum to provide2-methyl-5-fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl oxalate as atan solid.

Preparation of Final Title Compound

Scheme IV, step A; 1-cyclohexyl-2-(2-pyridyl)butan-1-one-4-al (0.32 g,1.31 mmol, prepared in Example 1, Scheme III, step C),2-methyl-5-fluoro-7-benzo(b)furan-3,4-dehydropiperidine oxalate (0.21 g,0.92 mmol, prepared in Scheme I, step D, above), methylene chloride (10mL), and acetic acid (0.22 mL, 3.93 mmol) were combined and treated withsodium triacetoxyborohydride (0.36 g, 1.70 mmol). The reaction mixturewas stirred at room temperature for 5 hours and then made basic with 1Nsodium hydroxide (5 mL). The reaction mixture was then extracted withmethylene chloride, the organic extracts were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by flash chromatography to provide the free base ofthe title compound (0.162 g, 38%).

The free base was dissolved in methanol and treated with oxalic acid(31.6 mg) and concentrated under vacuum to provide the final titlecompound, mp 188-189° C.

EXAMPLE 11 Preparation of4-(7-Benzo(b)furan-1,2,3,6-tetrahydropyridyl)-1-phenyl-2-phenyl-butan-1-olOxalate

Scheme IV, step C: A 50 mL round bottom flask was charged with4-(7-benzo(b)furan-3,4-dehydropiperidinyl)-1-phenyl-2-phenyl-butan-1-one(0.30 g, 0.59 mmol, prepared in Example 6) and methylene chloride (10mL). The solution was cooled to −78° C. and treated dropwise withdiisobutylaluminum hydride (1.76 mL of a 1 M solution in toluene, 1.76mmol). The reaction mixture was then warmed slowly to room temperatureover 2 hours and then stirred for 16 hours. The reaction mixture wasthen diluted with saturated potassium sodium tartrate solution and thenextracted with methylene chloride. The organic extracts were combined,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by flash chromatography to provide thefree base of the title compound (0.154 g). The free base was dissolvedin methanol, treated with oxalic acid (11 mg) and concentrated undervacuum to provide the title compound, mp 105-107° C.

EXAMPLE 12 Preparation of4-(4-Fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butaneOxalate

Preparation of 2-Pyridyl-1-cyclohexylethane

Scheme V, step A: 2-Picoline (5 g, 54 mmol) is dissolved in THF (100 mL)and cooled to −78° C. N-Butyllithium (40 mL of a 1.6M solution in THF,64.3 mmol) was added to the solution over 10 minutes. The reactionmixture was then warmed to room temperature for 5 minutes and thencooled back down to −78° C. Then cyclohexylmethyl bromide (10 g, 57mmol) was added, the reaction was warmed to room temperature and allowedto stir overnight. The reaction was then heated at reflux for 6 hoursand then cooled to room temperature. The solvent was removed undervacuum and water and ethyl acetate were then added to the residue. Thelayers were separated and the aqueous was extracted with ethyl acetate.The organic extracts were combined, dried over anhydrous magnesiumsulfate, filtered and concentrated to provide a dark oil. The oil waspurified by flash chromatography to provide 2-pyridyl-1-cyclohexylethane(9 g, 89%).

Preparation of 2-Pyridyl-3-cyclohexyl-butyraldehyde Diethyl Acetal

Scheme V, step B: 2-Pyridyl-1-cyclohexylethane (2 g, 10.6 mmol, preparedabove) was dissolved in THF (20 mL) and cooled to −78° C. N-Butyllithium(13 mL of a 1.6 M solution in THF, 21.2 mmol) was added to the cooledsolution. After stirring for 10 minutes, the cooling bath was removedand after 10 minutes, when the reaction had reached room temperature, itwas re-cooled to −78° C. Bromoacetaldehyde diethyl acetal (2.1 g, 10.6mmol) was then added and after one hour the cooling bath was removed.After 1.5 hours, n-Bu₄NBr was added and the reaction was then stirredovernight. Water was then added and the quenched reaction was extractedwith ethyl acetate (3 times). The organic extracts were combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by flash chromatography to provide2-pyridyl-3-cyclohexyl-butyraldehyde diethyl acetal (1.5 g, 46%).

Preparation of 4-Cyclohexyl-3-(2-pyridyl)-butyraldehyde

Scheme V, step C: 2-Pyridyl-3-cyclohexyl-butyraldehyde diethyl acetal(650 mg) was dissolved in acetone (10 mL), treated with HCl (a solutionof 2.5 mL concentrated HCl and 7.5 mL water) and the reaction wasstirred at room temperature overnight. 1N sodium hydroxide (30 mL) wasthen added and the neutralized reaction mixture was extracted with ethylacetate (2 times). The organic extracts were combined, dried overanhydrous magnesium sulfate, filtered and concentrated under vacuum toprovide 4-cyclohexyl-3-(2-pyridyl)-butyraldehyde (480 mg) as an oil.

Preparation of 2-(2-Bromo-5-fluorophenol)acetaldehyde Diethyl Acetal

Scheme I, step A: 2-Bromo-5-fluorophenol (15 g, 78.5 mmol),bromoacetaldehyde diethyl acetal (16.2 g, 82.5 mmol) and sodium hydride(3.8 g of a 60% dispersion, 94.2 mmol) were combined with DMF (100 mL)in a manner analogous to the procedure described in Example 1, Scheme I,step A, to provide 2-(2-bromo-5-fluorophenol)acetaldehyde diethyl acetal(21.8 a, 90%).

Preparation of 4-Fluoro-7-bromo-benzo(b)furan

Scheme I, step B: 2-(2-Bromo-5-fluorophenol)acetaldehyde diethyl acetal(21 g, prepared above) were combined with polyphosphoric acid (50 g) andchlorobenzene (250 mL) in a manner analogous to the procedure describedin Example 9, Scheme I, step B to provide 4-fluoro-7-bromo-benzo(b)furan(8 g).

Preparation of1-(t-Butoxycarbonyl)-4-(4-fluoro-7-benzo(b)furan)-4-hydroxy Piperidine

Scheme I, step C: 4-Fluoro-7-bromo-benzo(b)furan (5.58 g, 26 mmol) wascombined with magnesium (1.26 g, 52 mmol) in diethyl ether (100 mL) andthe mixture was stirred for 30 minutes. Then 1,2-dibromoethane (0.5 mL)was added. After 15 minutes an additional amount of 1,2-dibromoethane(1.7 mL) was added over 2 hours. It was then heated to gentle reflux forone hour and then cooled to room temperature.1-(t-Butoxycarbonyl)-4-piperidone (5.7 g, 23.6 mmol) dissolved indiethyl ether was then added to the reaction mixture and the reactionwas stirred overnight. Then ethyl acetate (100 mL) and water (200 mL)was added followed by addition of 1N HCl until the layers separated. Thelayers were separated and the aqueous was extracted with ethyl acetate(2 times). The organic extracts were combined, dried over anhydrousmagnesium sulfate, filtered and concentrated under vacuum to provide1-(t-butoxycarbonyl)-4-(4-fluoro-7-benzo(b)furan)-4-hydroxy piperidine(9.2 g).

Preparation of 4-Fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl

Scheme I, step D:1-(t-Butoxycarbonyl)-4-(4-fluoro-7-benzo(b)furan)-4-hydroxy piperidine(9.2 g, 28.8 mmol), p-toluenesulfonic acid (12.0 g, 63 mmol) and toluene(200 mL) was combined in a manner analogous to the procedure describedin Example 9, Scheme I, step D to provide4-fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl (4.1 g, 83%) as anoil.

Preparation of Final Title Compound

Scheme V, step D: 4-Fluoro-7-benzo(b)furan-3,4-dehydropiperidine (220mg), 4-cyclohexyl-3-(2-pyridyl)-butyraldehyde (201 mg, 0.82 mmol),acetic acid (0.14 mL, 2.46 mmol), sodium triacetoxyborohydride (226 mg,1.067 mmol) and methylene chloride (10 mL) were combined in a manneranalogous to the procedure described in Example 9, Scheme I, step D toprovide, after purification by flash chromatography (ethylacetate:hexane, 7:3 to 1:1, silica gel), the free base of the finaltitle compound (167 mg). The free base was treated with (34.8 mg) oxalicacid in methanol. The solution was concentrated under vacuum to providethe title compound, mp 110-115° C.

EXAMPLE 13 Preparation of4-(5-Fluoro-7-benzo(b)furan-piperidinyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-oneOxalate

Preparation of 4-Fluoro-7-benzo(b)furan-piperidine

Scheme I, step E: 5-fluoro-7-benzo(b)furan-3,4-dehydropiperidine (0.70g, 3.23 mmol, prepared in Example 9, Scheme I, step D) was dissolved inabsolute ethanol (30 mL) and treated with 10% palladium on carbon (0.21g) and NH₄CO₂ (0.71 g, 11.31 mmol). The reaction mixture was heated toreflux for 3 hours, cooled and then stirred at room temperature for 16hours. The reaction mixture was then filtered through Celite(diatomaceous earth) and the filtrate was concentrated under vacuum toprovide a clear oil (0.609 g). The oil was taken up in methanol, treatedwith oxalic acid (0.25 g) and then concentrated under vacuum to providea white solid. The white solid was then triturated with diethyl ether toprovide 4-fluoro-7-benzo(b)furan-piperidine (0.6 g), mp 210-211° C.

Preparation of Final Title Compound

Scheme IV, step A: 1-cyclohexyl-2-(2-pyridyl)butan-1-one-4-al (0.42 g(50% pure), 0.86 mmol, prepared in Example 1, Scheme II, step C),4-fluoro-7-benzo(b)furan-piperidine (0.19 g, 0.87 mmol, prepared inScheme I, step E, above), methylene chloride (15 mL), and acetic acid(0.15 mL, 2.6 mmol) were combined and treated with sodiumtriacetoxyborohydride (0.24 g, 1.12 mmol). The reaction mixture wasstirred at room temperature for 18 hours and then made basic with 1Nsodium hydroxide (5 mL). The reaction mixture was then extracted withmethylene chloride, the organic extracts were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by flash chromatography to provide the free base ofthe title compound (0.334 g, 85%).

The free base was dissolved in methanol and treated with oxalic acid (66mg) and concentrated under vacuum to provide the final title compound,mp 154-155° C.

The following Table I illustrates additional compounds of the presentinvention. The following compounds are readily prepared by one ofordinary skill in the art in a manner analogous to the proceduresdescribed hereinabove.

TABLE I Example Compound Melting Point 14

130-132° C. 15

123-125° C. 16

148-150° C. 17

118-120° C. 18

170-175° C. 19

185-188° C. 20

138-140° C. 21

118-120° C. 22

135-138° C. 23

190-191° C. 24

82-85° C. 25

82-85° C. 26

137-139° C. 27

85-92° C.

More specifically, the compound of Example 17 is prepared as follows:

Preparation of4-(4-Fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-2-(2-pyridyl)butan-1-oneOxalate

4-(4-fluoro-7-benzo(b)furan-3,4-dehydropiperidine (5 g, 23 mmol,prepared in example 12), 1-cyclohexyl-2-(2-pyridyl)butan-1-one-4-al (8.5g, 35 mmol, prepared in example 1, Scheme III, step C), methylenechloride (200 mL) and acetic acid (5.2 mL, 92 mmol) were combined andtreated with sodium triacetoxyborohydride (8.8 g, 41 mmol). The reactionmixture was stirred at room temperature for 2.5 hours and then madebasic with 1 N sodium hydroxide. The reaction mixture was then extractedwith methylene chloride. The organic extracts were combined, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified by flash chromatography (solvent: Ethyl acetate) toprovide the free base of the title compound (9.7 g, 94%) as an oil. Thefree base was dissolved in methanol and treated with 1 equivalent ofoxalic acid and concentrated under vacuum, to provide the final titlecompound, melting point 118-200° C.

Preparation of4-(4-Fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-2-(2-pyridyl)butan-1-one2HCl

4-(4-fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-2-(2-pyridyl)butan-1-one(493 mg, free base prepared above) was dissolved in diethyl ether (40ml) and an ether solution of saturated with HCl gas was added dropwiseuntil slightly acid as indicated by pH paper. This gave a filterablesolid of the title compound (494 mg, 86% yield) melting point 105-110°C. Mass Spec ESI+, M+1=447.2 (MW of free base=446.56), ¹H NMR (300 MHz,CDCl₃) δ 068-1.878 ppm (15H, m); 2.35-4.36 ppm (9H, m); 6.44-8.55 ppm(9H, m).

EXAMPLE 28 Preparation of 1-Cyclohexyl-2-phenylpropanol

Scheme VI, step A: To a solution of cyclohexylmagnesium chloride (50mmol) in 25 mL of Et₂O and 40 mL of THF at −5° C. was added a solutionof 2-phenylpropanaldehyde (5.36 g, 40 mmol) in 10 mL of THF. Thereaction mixture exothermed to 5° C. After stirring at room temperaturefor 75 min, the solution was poured onto ice cold 1 N HCl, extractedwith toluene, dried over MgSO₄, and concentrated to give the titlecompound as a colorless oil (6.15 g, 70%): ¹H NMR (d⁶-DMSO): δ 7.23-7.30(m, 2H, phenyl CH), 7.15-7.22 (m, 3H, phenyl CH), 4.17-4.51 (brs, 1H,—OH), 3.23-3.33 (m, 1H, R₂CHOH), 2.78 (dq, J=7.0 Hz, J=7.1 Hz, 1H,—CH(CH₃)Ph), 1.23-1.83 (m, 6H, cyclohexyl CH), 1.20 (d, J=6.9 Hz, 3H,—CH(CH ₃)Ph), 0.88-1.18 (m, 5H, cyclohexyl CH).

Preparation of Cyclohexyl 1-Phenylethyl Ketone

Scheme VI, step B: DMSO (118 mL, 1.6674 mol) was added dropwise to asolution of 126.42 g (0.579 mol) of 1-cyclohexyl-2-phenylpropanol in1737 mL of CH₂Cl₂ (cooled in a wet ice acetone bath). After 29 min,147.93 g (1.0422 mol) of P₂O₅ was added. After 11 min, the cooling bathwas removed. An aliquot quenched with Et₃N showed complete reactionwithin 3 h at RT. The reaction mixture was cooled in a wet ice acetonebath. Et₃N (282 mL, 2.0265 mol) was added dropwise to the cooledreaction mixture over a 30 min period. The cooling bath was removed andthe mixture was stirred overnight at RT. The reaction mixture wasquenched by dropwise addition of 500 mL of 3 N HCl (aq) (pH=0). Aftershaking in separatory funnel, the aqueous phase was removed. The organicphase was washed with 500 mL of 3 N HCl (aq) (pH=0), washed twice with 1L of 10% K₂CO₃ (aq) (pH=12;12), washed three times with 500 mL of NaOCl(aq) solution, washed with 1L of water, washed with 1 L of 25% NaCl(aq), dried over MgSO₄, gravity filtered and concentrated under vacuumwith dry ice trap to collect Me₂S. An amber oil of the title compound(107.01 g, 85.437 %) was obtained;

¹H NMR (d⁶DMSO): δ 7.30-7.37 (m, 2H, phenyl CH), 7.21-7.28 (m, 3H,phenyl CH), 4.08 (q, J=6.9 Hz, 1H, —CH(CH₃)Ph), 2.40-2.49 (m, 1H,cyclohexyl CH), 1.82-1.84 (m, 1H, cyclohexyl —CH₂), 1.67-169 (m, 1H,cyclohexyl —CH₂), 1.52-1.63 (m, 1H, cyclohexyl —CH₂), 1.34-1.43 (m, 1H,cyclohexyl —CH₂), 1.26 (d, J=6.9 Hz, 3H, —CH(CH ₃)Ph), 1.01-1.24 (m, 4H,cyclohexyl —CH₂).

Preparation of 2-Phenyl-2-methyl-4-pentenoyl Cyclohexane

Scheme VI, step C; A solution of 31.39 g (0.2797 mol) of t-BuOK in 100mL of THF was added dropwise to a solution of 55.00 g (0.2543 mol) ofcyclohexyl 1-phenylethyl ketone and 26.4 mL (0.3052 mol) of allylbromide in 136 mL of THF (cooled in a wet ice acetone bath). THFwashings (16 mL) were added to the reaction mixture. The cooling bathwas removed after addition. After reaction completion (2 h), thereaction mixture was quenched with 300 mL of 1 N HCl (pH=0) andextracted with 300 mL of heptane. The heptane extract was washed with10% NaHCO₃ (aq) (pH=9), dried over MgSO₄, gravity filtered andconcentrated under vacuum to afford 59.70 g (91.58%) of title compoundas an amber oil: ¹H NMR (d⁶-DMSO): δ 7.32-7.42 (m, 2H, phenyl CH),7.24-7.31 m, 3H, phenyl CH), 5.34-5.47 (m, 1H, —CH═CH₂), 5.02 (dd,J=17.1 Hz, J=2.1 Hz, 1H, —CH═CH—H (trans)), 4.97 (ddd, J=10.2 Hz, J=2.2Hz, J=1.0 Hz, 1H, —CH═CH—H (cis, W-coupling)), 2.66 (ddd, J=14.2 Hz,J=6.9 Hz, J=1.0 Hz, 1H, —CH ₂CH═CH₂), 2.59 (ddd, J=14.2 Hz, J=7.3 Hz,J=1.0 Hz, 1H, —CH ₂CH═CH₂), 2.38-2.49 (m, 1H, cyclohexyl CH), 1.48-1.69(m, 4H, cyclohexyl —CH ₂), 1.46 (s, 3H, —CH(CH ₃)Ph), 1.36-1.44 (m, 1H,cyclohexyl —CH ₂), 0.82-1.36 (m, 5H, cyclohexyl —CH ₂).

Preparation of 4-Cyclohexyl-3-methyl4-oxo-3-phenylbutyraldehyde

Scheme VI, step D: Ozone was bubbled through a cloudy mixture of 56.50 g(0.2204 mol) of 2-phenyl-2-methyl-4-pentenoyl cyclohexane and a smallamount (˜10 mg) of Sudan III in 220 mL of MeOH (cooled in a dry iceacetone bath at −20° C.) for 4 h until pink color turned to pale yellowcolor. After all of the olefin was consumed, Me₂S (50 mL) was added toreaction mixture. The cooling bath was removed. The exotherm rose to 38°C. and mixture was cooled in cooling bath until there was no exotherm.Then the cooling bath was removed and the mixture was stirred overnight.The reaction solution was concentrated under vacuum with dry ice trap tocollect excess Me₂S to afford 83.65 g of crude4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde dimethyl acetal as apink oil:

¹H NMR (d⁶-DMSO): δ 7.34-7.39 (m, 2H, phenyl CH), 7.24-7.30 (m, 3H,phenyl CH), 3.99 (dd, J=4.2 Hz, J=5.9 Hz, 1H, CH(OCH₃)₂), 3.14 (s, 3H,CH(OCH ₃)₂), 3.06 (s, 3H, CH(OCH ₃)₂), 2.34-2.43 (m, 1H, cyclohexyl CH),2.10-2.20 (m, 2H, —CH ₂CH(OCH ₃)₂), 1.55-1.67 (m, 1H, cyclohexyl —CH ₂),1.53 (s, 3H, R₂C(CH₃)Ph), 0.80-1.52 (m, 9H, cyclohexyl —CH ₂).

To a solution of 82.65 g (66.29 g, 0.2177 mol) of4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde dimethyl acetal in 539mL of acetone was added 539 mL of 3 N HCl (aq) at RT. After reactioncompletion (2 h), the mixture was concentrated to 426.5 g (or 1/3volume) of residue (RT −40° C.). The residue contained mostly water(pH=0) and was extracted twice with 300 mL of MTBE. The MTBE extract waswashed with 300 mL of 25% NaCl (aq), dried over MgSO₄, gravity filteredand concentrated to afford 54.92 g (97.65%) of title compound as a pinkoil: ¹H NMR (d⁶DMSO): δ 9.54 (t, J=2.0 Hz, 1H, —CHO), 7.36-7.45 (m, 2H,phenyl CH), 7.28-7.35 (m, 3H, phenyl CH), 2.95 (dd, J=16.6 Hz, J=1.9 Hz,1H, CH ₂CHO), 2.85 (dd, J=16.6 Hz, J=1.7 Hz, 1H, CH ₂CHO), 2.41-2.49 (m,1H, cyclohexyl CH), 1.72 (s, 3H, R₂C(CH₃)Ph), 0.85-1.66 (m, 10H,cyclohexyl —CH ₂).

Utilizing the aldehyde prepared in Example 28, the following compoundslisted in Table II can readily be prepared by one of ordinary skill inthe art in a manner analogous to the procedures described hereinabove.The compounds in Table II were not actually prepared.

TABLE II Example Compound 29

30

31

32

33

34

35

36

The following Table III provides additional compounds according to thepresent invention which can be prepared by one of ordinary skill in theart in a manner analogous to the procedures described hereinabove.

TABLE III Example Compound Melting Point 37a

62-65° C. 37b

160-165° C. 38a

94-98° C. 38b

52-55° C. 39

105-108° C. 40

95-98° C. 41

175-178° C. 42

100-102° C. 43a

125-127° C. 43b

130-132° C. 44

120-125° C. 45

Anal. C,H,N 46

176-179° C. 47

115-120° C. 48

106-108° C. 49

166-170° C. 50

92-95° C. 51

175-180° C. 52

150-160° C. 53

Enantiomer 1 90-95° C. 54

Enantiomer 2 85-90° C. 55

85-90° C. 56

Enantiomer 1 68-70° C. 57

Enantiomer 2 90-94° C. 58a

Enantiomer 1 95-98° C. 58b

Enantiomer 2 97-100° C. 59a

Enantiomer 1 109-111° C. 59b

Enantiomer 2 158-160° C. 60a

Enantiomer 1 105-110° C. 60b

Enantiomer 2 115-120° C. 61

208-209° C. 62

110-115° C. 63a

79-81° C. 63b

75-77° C. 63c

84-86° C. 63d

85-87° C. 64

167-170° C. 65a

80-85° C. 65b

85-90° C. 66

149-150° C. 67

163-165° C. 68

108-110° C. 69a

100-107° C. 69b

102-107° C. 70

160-161° C. 71a

184-185° C. 71b

100-105° C. 72

205-206° C. 73

115-120° C. 74

155-157° C. 75

91° C. 76

145-156° C. 77

78

79

80a

78-82° C. 100% ee 80b

71-75° C. 95.8% ee 80c

80-84 95.4% ee 80d

90-94° C. 98.0% ee 81a

155-160° C. 81b

155-160° C. 82

110-112° C. 83

110° C. 84

95-100° C. 85

110-112° C. 86

157-160° C. 87

88

89

203° C.(dec.) 90

82-85° C. 91

92

90-95° C. 93

255° C.(dec.) 94

130-133° C. 95

Not prepared 96

Not prepared 97

Not prepared 98

Not prepared 99

Not prepared

EXAMPLE 100

Preparation of:

NaCN (2.85 g, 0.058 mol) was suspended in DMSO (22 mL) and heated to140° C. To the stirring suspension was added 4-chlorotetrahydropyran(5.0 g, 0.041 mol). The reaction mixture was stirred at 135-145° C. for1.5 hours and then cooled to room temperature. The reaction was dilutedwith water, extracted with ethyl acetate, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue was passedthrough a silica gel plug eluting with hexane/ethyl acetate (1:1) toprovide 4-cyanotetrahydropyran (0.65 g).

Picoline (0.58 mL, 5.85 mmol) was dissolved in THF (15 mL) and cooled to−78° C. The solution was treated with n-BuLi (3.84 mL of a 1.6 Nsolution in THF, 6.14 mmol). The solution was warmed to room temperaturefor 30 minutes and then recooled to −78° C. 4-cyanotetrahydropyran (0.65g, 5.85 mmol, prepared above) dissolved in THF (5 mL) was added dropwiseto the stirring solution. The reaction mixture was then warmed to roomtemperature and stirred for about 20 hours. It was then poured intowater, stirred for 15 minutes and extracted with ethyl acetate (3×50mL). The organic extracts were combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by flash chromatography (silica gel, ethyl acetate) to providethe following ketone (0.78 g):

7-benzo(b)thiophene-1,2,3,6-tetrahydropyridyl (1.39 g, 6.40 mmol,prepared in example 1) was dissolved in methylene chloride (20 mL) andtreated with 50% aqueous chloroacetaldehyde (1.64 mL, 12.9 mmol)followed by acetic acid (0.74 mL, 12.9 mmol) and sodiumtriacetoxyborohydride (2.73 g, 12.9 mmol). The reaction mixture wasstirred at room temperature for one hour and then treated with 1N sodiumhydroxide. The quenched reaction was extracted with methylene chloride,the organic extracts were dried over anhydrous sodium sulfate, filteredand concentrated under vacuum to provide the following7-benzo(b)thiophene derivative as a brown oil:

The ketone (1.0 g, 4.88 mmol, prepared above) was dissolved in DMF (20mL) and cooled to 0° C. It was then treated with sodium hydride (60%dispersion, 0.20 g, 5.12 mmol) and stirred for 30 minutes at 0° C. andthen warmed to room temperature. The 7-benzo(b)thiophene derivative(1.42 g, 5.12 mmol, prepared above) was dissolved in DMF (5 mL) andadded to the reaction. The reaction mixture was then stirred at roomtemperature for 3 hours. Potassium iodide (0.1 g) was added and thereaction mixture was heated to 50° C. for 2 hours. The reaction was thenquenched with water and extracted with ethyl acetate. The organicextracts were combined, washed with water (10 times), then brine, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by flash chromatography (silica gel, 10%methanol/ethyl acetate) to provide the free base of the title compound.The free base was treated with oxalic acid under standard conditions toprovide the title compound, mp 128-130° C.

EXAMPLE 101

Preparation of:

4-(7-benzo(b)thiophene-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-one(0.20 g, 0.45 mmol, prepared in example 1), and hydroxylaminehydrochloride (0.31 g, 4.5 mmol) were combined with water (7 mL) andethanol (30 mL). The reaction mixture was heated at reflux for about 24hours and then partially concentrated. The reaction mixture was thendiluted with ethyl acetate, the organic layer was separated, washed withwater, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by flash chromatography (silicagel, 5% methanol/ethyl acetate) to provide the title compound (0.119 g),mp 88-92° C.

EXAMPLE 102

Preparation of:

The title compound prepared in example 101 (0.30 g, 0.65 mmol) wasdissolved in diethyl ether (50 mL) and treated with lithium aluminumhydride (0.10 g, 2.61 mmol, LAH). The reaction was stirred for about 18hours and additional LAH (0.1 g, 2.61 mmol) was added. The reactionmixture was then heated at reflux for about 5 hours, then cooled andquenched with saturated potassium sodium tartrate solution (50 mL). Themixture was then extracted with ethyl acetate, the combined organicextracts were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by flashchromatography (silica gel, 5% methanol/methylene chloride, 2MNH₃) toprovide the purified free base (0.09 g). The free base was treated withoxalic acid to provide the title compound, mp 128° C.

EXAMPLE 103

Preparation of:

The title compound was prepared from4-(4-fluoro-7-benzo(b)furan-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-one(prepared in example 17) and hydroxylamine hydrochloride in a manneranalogous to the procedure described in example 101 above, mp 101-105°C.

EXAMPLE 104

Preparation of:

The title compound was prepared in a manner analogous to the proceduredescribed in example 102 from the title compound prepared in example103, and treatment with HCl rather than oxalic acid to provide the HClsalt.

EXAMPLE 105

Preparation of:

The title compound was prepared from4-(7-benzo(b)furan-3,4-dehydropiperidinyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-one(prepared in example 5) and hydroxylamine hydrochloride in a manneranalogous to the procedure described in example 101 above, (0.38 g), mp85-90° C.

EXAMPLE 106

Preparation of:

The title compound was prepared from the titel compound prepared inexample 105 in a manner analogous to the procedure described in example102, mp 152° C. (dec).

EXAMPLE 107

Preparation of:

The following aldehyde:

(0.20 g, 0.69 mmol) was combined with7-benzo(b)thiophene-1,2,3,6-tetrahydropyridyl (0.15 g, 0.76 mmol,prepared in example 1) in methylene chloride (20 mL) and stirred for 20minutes. The reaction mixture was then treated with acetic acid (0.06mL, 1.04 mmol) and sodium triacetoxyborohydride (0.19 g, 0.90 mmol) andstirred for 2 hours. The reaction was then quenched with 1N sodiumhydroxide and extracted with methylene chloride. The organic extractswere combined, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by flashchromatography (silica gel, 50% ethyl acetate/hexane) to provide thefree base of the title compound (0.117g). The free base was treated withoxalic acid (17.4 mg) under standard conditions to provide the titlecompound (0.08g), mp 122-125° C.

EXAMPLE 108

Preparation of

A 50 mL round bottom flask was charged with4-(7-benzo(b)thiophene-3,4-dehydropiperidinyl)-1-(2-pyridyl)-2-cyclohexyl-butan-1-one(0.50 g, 1.12 mmole, prepared in example 1) and dimethylsulfoxide (10mL). The solution was treated with potassium hydroxide (0.20 g, 3.56mmole) dissolved in tetrahydrofuran/water (5 mL/1 mL) at roomtemperature. The solution was then warmed to 50° C. for 30 minutes.Then, 36% aqueous formaldehyde solution (0.09 g, 1.12 mmole) was added.The reaction mixture was stirred at room temperature for 3 hours. Thereaction mixture was diluted with ethyl acetate. The organic layer wasseparated and dried over anhydrous sodium sulfate, then filtered andconcentrated under vacuum. The residue was purified by flashchromatography to provide the free base the title compound (0.03 g). Thefree base form was dissolved in methanol and treated with oxalic acid(5.9 mg) to obtain the title compound, mp 110° C.

EXAMPLE 109

Preparation of

A 50 mL round bottom flask was charged with4-(7-benzo(b)thiophene-3,4-dehydropiperidinyl)-1-(2-pyridyl)-2-cyclohexyl-butan-1-one(0.50 g, 1.12 mmole, prepared in example 1) and dimethylsulfoxide (10mL). The solution was treated with potassium hydroxide (0.20 g, 3.56mmole) dissolved in tetrahydrofuran/water (5 mL/1 mL) at roomtemperature. The solution was warmed to 50° C. for 30 minutes. Then, 36%aqueous formaldehyde solution (0.09 g, 1.12 mmole) was added. Thereaction mixture was stirred at room temperature for 3 hours. Thereaction mixture was diluted with ethyl acetate. The organic layer wasseparated and dried over anhydrous sodium sulfate, then filtered andconcentrated under vacuum. The residue was purified by flashchromatography to provide the free base the title compound (0.04 g). Thefree base form was dissolved in methanol and treated with oxalic acid(7.5 mg) to obtain the title compound, mp 115-120° C. (dec).

EXAMPLE 110

Preparation

A 50 mL round bottom flask was charged with2-methoxy-2-phenylacetophenone and N,N-dimethylformamide (10 mL). Thesolution was cooled to 0° C. and was treated with 60% suspension ofsodium hydride in oil (0.18 g, 4.42 mmole). The slurry was warmed slowlyto room temperature over 45 minutes. Then1-[4-(7-benzo(b)thiophene-3,4-dehydropiperidinyl]-2-chloroethane (0.48g, 1.73 mmole) dissolved in N,N-dimethylformamide (5 mL) was addeddropwise. The reaction mixture was stirred at room temperature for 16hours. The reaction mixture was then diluted with water and extractedwith ethyl acetate. The organic layer was washed with water andsaturated sodium chloride solution. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by flash chromatography to provide the free base ofthe title compound (0.024 g). The free base was dissolved in methanol,treated with oxalic acid (4.6 mg) and concentrated under vacuum toprovide the title compound, mp 100-102° C.

Serotonin-1_(A) Receptor and Serotonin-2_(A) Receptor Activity

The compounds of the present invention are active at the serotonin-1_(A)receptor and at the serotonin-2_(A) receptor, particularly asantagonists and as partial agonists at that receptor. Previously knowncompounds with that activity typically have the disadvantage ofpossessing other non-serotonin related central nervous system activitiesas well. It is now well understood by pharmacologists and physiciansthat pharmaceuticals which have a single physiological activity, orwhich are much more active in the desired activity than in their otheractivities, are much more desirable for therapy than are compounds whichhave multiple activities at about the same dose.

The 5-HT_(1A) receptor binding potency and the 5-HT_(2a) receptorbinding potency of the present compounds are measured by techniques wellknown in the art. For example, the 5-HT_(1A) receptor binding potency ismeasured by a modification of the binding assay described by Taylor, etal. (J. Pharmacol. Exp. Ther. 236, 118-125, 1986); and Wong, et al.,Pharm. Biochem. Behav. 46, 173-77 (1993). Membranes for the bindingassay are prepared from male Sprague-Dawley rats (150-250 g). Theanimals are killed by decapitation, and the brains are rapidly chilledand dissected to obtain the hippocampi. Membranes from the hippocampiare either prepared that day, or the hippocampi are stored frozen (−70°)until the day of preparation. The membranes are prepared by homogenizingthe tissue in 40 volumes of ice-cold Tris-HCl buffer (50 mM, pH 7.4 at22°) using a homogenizer for 15 sec., and the homogenate is centrifugedat 39800×g for 10 min. The resulting pellet is then resuspended in thesame buffer, and the centrifugation and resuspension process is repeatedthree additional times to wash the membranes. Between the second andthird washes the resuspended membranes are incubated for 10 min. at 37°to facilitate the removal of endogenous ligands. The final pellet isresuspended in 67 mM Tris-HCl, pH 7.4, to a concentration of 2 mg oftissue original wet weight/200 μl. This homogenate is stored frozen(−70°) until the day of the binding assay. Each tube for the bindingassay has a final volume of 800 μl and contains the following: Tris-HCl(50 mM), pargyline (10 μM), CaCl₂ (3 mM), [³H]8-OH-DPAT (1.0 nM),appropriate dilutions of the drugs of interest, and membraneresuspension equivalent to 2 mg of original tissue wet weight, for afinal pH of 7.4. The assay tubes are incubated for either 10 min. or 15min. at 37°, and the contents are then rapidly filtered through GF/Bfilters (pretreated with 0.5% polyethylenimine), followed by four one-mlwashes with ice-cold buffer. The radioactivity trapped by the filters isquantitated by liquid scintillation spectrometry, and specific[3H]8-OH-DPAT binding to the 5-HT1A sites is defined as the differencebetween [3H]8-OH-DPAT bound in the presence and absence of 10 μM 5-HT.

IC50 values, i.e., the concentration required to inhibit 50% of thebinding, are determined from 12-point competition curves using nonlinearregression (SYSTAT, SYSTAT, Inc., Evanston, Ill.). IC50 values areconverted to Ki values using the Cheng-Prusoff equation (Biochem.Pharmacol., 22, 3099-3108 (1973).

Additional binding assays of some of the present compounds are carriedout by an assay method which uses a cloned cell line which expresses theserotonin-1A receptor, rather than the hippocampal membranes. Suchcloned cell lines have been described by Fargin, et al., J.Bio. Chem.,264, 14848-14852 (1989), Aune, et al., J. Immunology, 151, 1175-1183(1993), and Raymond, et al., Naunyn-Schmiedeberg's Arch. Pharmacol.,346, 127-137 (1992). Results from the cell line assay are substantiallyin agreement with results from the hippocampal membrane assay.

As was reported by R. L. Weinshank, et al., WO93/14201, the 5-HT1Areceptor is functionally coupled to a G-protein as measured by theability of serotonin and serotonergic drugs to inhibit forskolinstimulated cAMP productionin NIH3T3 cells transfected with the 5-HT1Areceptor. Addenylate cyclase activity is determined using standardtechniques. A maximal effect is achieved by serotonin. An Emax isdetermined by dividing the inhibition of a test compound by the maximaleffect and determining a percent inhibition. (N. Adham, et al., supra,;R. L. Weinshank, et al., Proceedings of the National Academy of Sciences(USA), 89,3630-3634 (1992)), and the references cited therein.

[³⁵S]GTPγS Binding Method

Agonist activation of G protein-coupled receptors results in the releaseof GDP (guanosine-5′-diphosphate) from the γ-subunit of the G proteinand the subsequent binding of GTP (guanosine-5′-triphosphate). Thebinding of the stable analogue [³⁵S]GTPγS (guanosine5′-O-[3-thiotriphosphate]) can be used as an indicator of this receptoractivation (see Wieland, T., Jakobs, K. H., 1994. Measurement ofreceptor-stimulated guanosine 5′-O-(γ-thio)triphosphate binding by Gproteins. Methods Enzymol. 237, 3-13.). EC₅₀ and efficacy (E_(max))values can be determined. Similarly, antagonists will inhibitagonist-stimulated [³⁵S]GTPγS binding. From these experiments, IC₅₀values, converted to a dissociation constant, e.g. K_(i), and efficacy(E_(max)) values can be determined by one of ordinary skill in the art.

Measurement of cAMP Formation

Transfected NIH3T3 cells (estimated Bmax from one point competitionstudies=488 fmol/mg of protein) are incubated in DMEM, 5 mMtheophylline, 10 mM HEPES (4-[2-hydroxyethyl]-1-piperazineethanesulfonicacid) and 10 μM pargyline for 20 minutes at 37° C., 5% carbon dioxide.Drug dose-effect curves are then conducted by adding 6 different finalconcentrations of drug, followed immediately by the addition offorskolin (10 mM). Subsequently, the cells are incubated for anadditional 10 minutes at 37° C., 5% carbon dioxide. The medium isaspirated and the reaction is stopped by the addition of 100 mMhydrochloric acid. To demonstrate competitive antagonism, adose-response curve for 5-HT is measured in parallel, using a fixed doseof methiothepin (0.32 mM). The plates are stored at 4° C. for 15 minutesand then centrifuged for 5 minutes at 500×g to pellet cellular debris,and the supernatant is aliquoted and stored at −20° C. before assessmentof cAMP formation by radioimmunoassay (cAMP radioimmunoassay kit;Advanced Magnetics, Cambridge, Mass.). Radioactivity is quantified usinga Packard COBRA Auto Gamma counter, equipped with data reductionsoftware. Representative compounds are tested for 5-HT_(1A) receptorantagonist activity in the cAMP assay.

5HT_(1a) Antagonist, In Vivo Tests

a) 5HT_(1a) Antagonism Subcutaneous Test

Compounds ware tested over a range of subcutaneous doses for activity inblocking the B-OH-DPAT induced behaviors and hypothermia. Lower lipretraction (LLR) and flat body posture (FBP) are recorded in maleSprague Dawley rats (˜250 grams from Harlan Sprague Dawley). Both LLRand FBP are measured on a scale of 0-3 (Wolff et al, 1997). In the LLRbehavioral assay, “0” indicates normal lip position; “1” indicates aslight separation of the lips; “2” indicates that the lips are open withsome teeth visible; “3” indicates that the lips are fully open with allthe front teeth exposed. In the FBP assay, a score of “0” indicatesnormal body posture; “1” indicates that the stomach is on the floor withthe back in its normal rounded position; “2” indicates that the stomachis on the floor with the back straightened and rising from the shouldersto the hips; “3” indicates that the stomach is pressed into the floorand the back is flattened with the shoulders and hips even. Core bodytemperature is recorded by rectal probe inserted 5.0 cm immediatelyafter the behavioral measures. Rats are injected subcutaneous withcompound (at 0, 0.3, 1.0 and 3.0 mg/kg) 35 minutes before scoring andthe 8-OH-DPAT (0.1 mg/kg subcutaneous) is injected 20 minutes beforescoring.

b) 5HT_(1a) Agonist Subcutaneous Test

The compounds are also tested at a high dose of 10 mg/kg subcutaneousalone to see if they induced 5HT_(1a) agonist-like hypothermia.

The efficacy of the compounds of the invention to inhibit the reuptakeof serotonin is determined by a paroxetine binding assay, the usefulnessof which is set out by Wong, et al., Neuropschopharmacology, 8, 23-33(1993). Synaptosomal preparations from rat cerebral cortex are made fromthe brains of 100-150 g Sprague-Dawley rats which are killed bydecapitation. The cerebral cortex is homogenized in 9 volumes of amedium containing 0.32 M sucrose and 20 μM glucose. The preparations areresuspended after centrifugation by homogenizing in 50 volumes of coldreaction medium (50 μM sodium chloride, 50 μM potassium chloride, pH7.4) and centrifuging at 50,000 g for 10 minutes. The process isrepeated two times with a 10-minute incubation at 37° C. between thesecond and third washes. The resulting pellet is stored at −70° C. untiluse. Binding of ³H-paroxetine to 5-HT uptake sites is carried out in 2ml reaction medium containing the appropriate drug concentration, 0.1 nM³H-paroxetine, and the cerebral cortical membrane (50 μg protein/tube).Samples are incubated at 37° C. for 30 minutes; those containing 1 μMfluoxetine are used to determine nonspecific binding of ³H-paroxetine.After incubation, the tubes are filtered through Whatman GF/B filters,which are soaked in 0.05% polyethylenimine for 1 hour before use, usinga cell harvester by adding about 4 ml cold Tris buffer (pH 7.4),aspirating, and rinsing the tubes three additional times. Filters arethen placed in scintillation vials containing 10 ml scintillation fluid,and the radioactivity is measured by liquid scintillationspectrophotometry.

The pharmacological activities which have been described immediatelyabove provide the mechanistic basis for the pharmaceutical utility ofthe compounds described in this document. A number of pharmaceuticalutilities will be described below.

Throughout this document, the person or animal to be treated will bedescribed as the “subject”, and it will be understood that the mostpreferred subject is a human. However, it must be noted that the studyof adverse conditions of the central nervous system in non-human animalsis only now beginning, and that some instances of such treatments arecoming into use. For example, fluoxetine, and perhaps other serotoninreuptake inhibitors, are being used in companion animals such as dogsfor the treatment of behavioral problems and the like. Accordingly, useof the present compounds in non-human animals is contemplated.

It will be understood that the dosage ranges for other animals willnecessarily be quite different from the doses administered to humans,and accordingly that the dosage ranges described below in the section ontobacco withdrawal must be recalculated. For example, a small dog may beonly {fraction (1/10)}th of a typical human's size, and it willtherefore be necessary for a much smaller dose to be used. Thedetermination of an effective amount for a certain non-human animal iscarried out in the same manner described below in the case of humans,and veterinarians are well accustomed to such determinations.

The activity of the compounds at the serotonin-1A receptor provides amethod of affecting the serotonin-1 A receptor which comprisesadministering to a subject in need of such treatment an effective amountof a compound of formula I. Reasons for the necessity of affecting theserotonin-1A receptor will be described in detail below, but in allcases the effect on the serotonin-1A receptor is brought about throughthe compounds' potency as antagonists or partial agonists at thatreceptor. A subject in need of a modification of the effects of the5-HT_(1A) receptor is one having one or more of the specific conditionsand problems to be further described, or a condition or problem not yetrecognized as created by an imbalance or malfunction of the 5-HT_(1A)receptor, since research on the central nervous system is presentlyongoing in many fields and newly discovered relationships betweenreceptors and therapeutic needs are continually being discovered.

An effective amount of a compound for affecting the serotonin-1Areceptor is the amount, or dose, of the compound which provides thedesired effect in the subject under diagnosis or treatment. Theeffective amount of compound to be administered, in general, is fromabout 1 to about 200 mg/day; as usual, the daily dose may beadministered in a single bolus, or in divided doses, depending on thejudgment of the physician in charge of the case. A more preferred rangeof doses is from about 5 to about 100 mg/day; other dosage ranges whichmay be preferred in certain circumstances are from about 10 to about 50mg/day; from about 5 to about 50 mg/day; from about 10 to about 25mg/day; and a particularly preferred range is from about 20 to about 25mg/day.

The amount is an individualized determination, and physicians are wellaccustomed to adjusting effective amounts of pharmaceuticals based onobservations of the subject. The effective amount of the presentcompounds is discussed in some detail below, in the discussion about thetreatment of tobacco withdrawal symptoms, and that discussion isapplicable, in an analogous manner to the determination of the effectiveamount in all treatment methods.

In a manner analogous to the above, the activity of the compounds at theserotonin-2A receptor provides a method of affecting the serotonin-2Areceptor which comprises administering to a subject in need of suchtreatment an effective amount of a compound of formula I.

Further, the activity of compounds of formula I in the inhibition of thereuptake of serotonin provides a method of inhibiting the reuptake ofserotonin comprising administering to a subject in need of suchtreatment an effective amount of a compound of that formula. Aneffective amount of a compound for inhibiting the reuptake of serotoninis the amount, or dose, of the compound which provides the desiredeffect in the subject under diagnosis or treatment. The amount is anindividualized determination, and physicians are well accustomed toadjusting effective amounts of pharmaceuticals based on observations ofthe subject. It is now known that numerous physiological and therapeuticbenefits are obtained through the administration of drugs which inhibitthe reuptake of serotonin. The treatment of depression with drugs of theclass of which fluoxetine is the leader has become perhaps the greatestmedical breakthrough of the past decade. Numerous other treatmentmethods carried out by the administration of the compounds of formula Iwill be set out in detail below. Again, the effective amount of acompound for the inhibition of serotonin reuptake, or for a specifictherapeutic method which depends on the inhibition of reuptake, isdetermined in the manner analogous to that described below under theheading of smoking withdrawal.

The unique combination of 5-HT_(1A) receptor activity, 5-HT_(2A)receptor activity, and serotonin reuptake inhibition possessed by thecompounds of the invention afford a method of providing to a subjectboth physiological activities with a single administration of a compoundof that formula. It is believed that the present compounds areadvantageous in that they provide all three physiological effects in asingle drug. It is presently believed that the result of administrationof a compound of formula I is to provide physiological and therapeutictreatment methods which are typical of those provided by presently knownserotonin reuptake inhibitors, but with enhanced efficacy, quicker onsetof action and reduced side effects.

The activities of compounds of formula I at the 5-HT_(1A) receptor, the5-HT_(2A) receptor, and in reuptake inhibition are of comparablepotencies, so a single effective amount as defined hereinabove foraffecting the serotonin-1A receptor, the serotonin-2A receptor, or forinhibiting the reuptake of serotonin, is effective for affecting theserotonin-1A receptor, the serotonin-2A receptor, and for inhibiting thereuptake of serotonin in a subject.

Further discussion of specific therapeutic methods provided by theactivity compounds of formula I, and the diseases and conditionsadvantageously treated therewith, are provided below.

Tobacco or Nicotine Withdrawal

It is well known that the chronic administration of nicotine results intolerance and, eventually, dependence. The use of tobacco has becomeextremely widespread in all countries, despite the well known adverseeffects of the use of tobacco in all its forms. Thus, it is clear thattobacco use is extremely habit-forming, if not addictive, and that itsuse provides sensations to the user which are pleasant and welcome, eventhough the user may be fully aware of the drastic long term ill effectsof its use.

Rather recently, vigorous campaigns against the use of tobacco havetaken place, and it is now common knowledge that the cessation ofsmoking brings with it numerous unpleasant withdrawal symptoms, whichinclude irritability, anxiety, restlessness, lack of concentration,lightheadedness, insomnia, tremor, increased hunger and weight gain,and, of course, a craving for tobacco.

At the present time, probably the most widely used therapy to assist thecessation of tobacco use is nicotine replacement, by the use of nicotinechewing gum or nicotine-providing transdermal patches. It is widelyknown, however, that nicotine replacement is less effective withouthabit-modifying psychological treatment and training.

Thus, the present method of preventing or alleviating the symptomscaused by withdrawal or partial withdrawal from the use of tobacco or ofnicotine comprises the previously discussed method of affecting theserotonin-1A receptor, in that the treatment method comprises theadministration of an effective amount of one of the serotonin-1Areceptor-active compounds of formula I to the subject. The method of thepresent invention is broadly useful in assisting persons who want tocease or reduce their use of tobacco or nicotine. Most commonly, theform of tobacco use is smoking, most commonly the smoking of cigarettes.The present invention is also helpful, however, in assisting in breakingthe habit of all types of tobacco smoking, as well as the use of snuff,chewing tobacco, etc. The present method is also helpful to those whohave replaced, or partially replaced, their use of tobacco with the useof nicotine replacement therapy. Thus, such subjects can be assisted toreduce and even eliminate entirely their dependence on nicotine in allforms.

A particular benefit of therapy with the present compounds is theelimination or reduction of the weight gain which very often resultsfrom reducing or withdrawing from use of tobacco or nicotine.

It will be understood that the present invention is useful forpreventing or alleviating the withdrawal symptoms which afflict subjectswho are trying to eliminate or reduce their use of tobacco or nicotine.The common withdrawal symptoms of such people include, at least,irritability, anxiety, restlessness, lack of concentration, insomnia,nervous tremor, increased hunger and weight gain, light-headedness, andthe craving for tobacco or nicotine. The prevention or alleviation ofsuch symptoms, when they are caused by or occur in conjunction withceasing or reducing the subject's use of tobacco or nicotine is adesired result of the present invention and an important aspect of it.

The invention is carried out by administering an effective amount of acompound of formula I to a subject who is in need of or carrying out areduction or cessation of tobacco or nicotine use.

It will be understood that the effective amount for a given subject isalways to be set by the judgment of the attending physician, and thatthe dose is subject to modification based on the size of the subject,the lean or fat nature of the subject, the characteristics of theparticular compound chosen, the intensity of the subjects tobacco habit,the intensity of the subjects withdrawal symptoms, and psychologicalfactors which may affect the subject's physiological responses. Thus,the effective amount is the amount required to prevent or alleviate thesymptoms of withdrawal or partial withdrawal in the subject undertreatment.

In effecting treatment of a subject as described herein, a compound offormula I can be administered in any form or mode which makes thecompound bioavailable in effective amounts, including oral andparenteral routes. For example, compounds of formula I can beadmininstered orally, subcutaneously, intramuscularly, intravenously,transdermally, intranasally, rectally, and the like. Oral administrationis the preferred route for compounds of formula I.

The effect of compounds in alleviating the symptoms of nicotinewithdrawal is evaluated in rats by an auditory startle test, which iscarried out as follows.

Procedures for Nicotine Withdrawal Studies

Animals: Male Long Evans rats are individually housed in a controlledenvironment on a 12 hour light-dark cycle and are given free access tofood (Purina Rodent Chow) and water. All treatment groups contain 8-10rats.

Chronic Nicotine Treatment: Rats are anesthetized with halothane andAlzet osmotic minipumps (Alza Corporation, Palo Alto, Calif., Model2ML2) are implanted subcutaneously. Nicotine ditartrate is dissolved inphysiological saline. Pumps are filled with either nicotine ditartrate(6 mg/kg base/day) or physiological saline. Twelve days followingimplantation of pumps, rats are anesthetized with halothane and thepumps are removed.

Auditory Startle Response: The sensory motor reactions [auditory startleresponse (peak amplitude Vmax)] of individual rats is recorded using SanDiego Instruments startle chambers (San Diego, Calif.). Startle sessionsconsist of a 5-minute adaptation period at a background noise level of70±3 dBA immediately followed by 25 presentations of auditory stimuli(120±2 dBA noise, 50 ms duration) presented at 8-second intervals. Peakstartle amplitudes are then averaged for all 25 presentations of stimulifor each session. Auditory startle responding is evaluated daily at 24hour intervals on days 1-4 following nicotine withdrawal.

Combination With Reuptake Inhibitors

A further application of the compounds of formula I is their use incombination with a serotonin reuptake inhibitor to potentiate the actionof those drugs by increasing the availability of serotonin, as well asnorepinephrine and dopamine, in the brain of patients to whom the drugcombination is administered. Typical and appropriate reuptake inhibitors(SRI) are fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram,fluvoxamine and paroxetine. Accordingly, the present invention providesa method for potentiating the action of a serotonin reuptake inhibitor,particularly one of the group consisting of fluoxetine, duloxetine,venlafaxine, milnacipran, citalopram, fluvoxamine and paroxetine, inincreasing the availability of serotonin, norepinephrine and dopamine inthe brain, comprising administering said serotonin reuptake inhibitor incombination with a compound of formula I. The invention also providespharmaceutical compositions which comprise a serotonin reuptakeinhibitor in combination with a compound of formula I, and a method oftreating a pathological condition which is created by or is dependentupon decreased availability of serotonin, dopamine or norepinephrine,which method comprises administering the same adjunctive therapy to apatient in need of such treatment.

It will be understood that, while the compounds of formula Iindividually provide the benefit of the combination of serotoninreuptake inhibitors and serotonin-1A antagonists and serotonin-2Aantagonists, it is entirely possible to administer a compound of formulaI in combination with a conventional serotonin reuptake inhibitor inorder to obtain still further enhanced results in potentiating serotoninreuptake inhibition. Examples of representative serotonin reuptakeinhibitors include but are not limited to the following:

Fluoxetine, N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine,is marketed in the hydrochloride salt form, and as the racemic mixtureof its two enantiomers. U. S. Pat. No. 4,314,081 is an early referenceon the compound. Robertson, et al., J. Med. Chem. 31, 1412 (1988),taught the separation of the R and S enantiomers of fluoxetine andshowed that their activity as serotonin uptake inhibitors is similar toeach other. In this document, the word “fluoxetine” will be used to meanany acid addition salt or the free base, and to include either theracemic mixture or either of the R and S enantiomers.

Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, isusually administered as the hydrochloride salt and as the (+)enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which showsits high potency. The word “duloxetine” will be used here to refer toany acid addition salt or the free base of the molecule.

Venlafaxine is known in the literature, and its method of synthesis andits activity as an inhibitor of serotonin and norepinephrine uptake aretaught by U.S. Pat. No. 4,761,501. Venlafaxine is identified as compoundA in that patent.

Milnacipran (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide)is taught by U.S. Pat. No. 4,478,836, which prepared milnacipran as itsExample 4. The patent describes its compounds as antidepressants. Moret,et al., Neuropharmacology 24, 1211-19(1985), describe itspharmacological activities.

Citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile,is disclosed in U.S. Pat. No. 4,136,193 as a serotonin reuptakeinhibitor. Its pharmacology was disclosed by Christensen, et al., Eur.J. Pharmacol. 41, 153 (1977), and reports of its clinical effectivenessin depression may be found in Dufour, et al., Int. Clin.Psychopharmacol. 2, 225 (1987), and Timmerman, et al., ibid., 239.

Fluvoxamine, 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone0-(2-aminoethyl)oxime, is taught by U.S. Pat. No. 4,085,225. Scientificarticles about the drug have been published by Claassen, et al., Brit.J. Pharmacol. 60, 505 (1977); and De Wilde, et al., J. Affective Disord.4, 249 (1982); and Benfield, et al., Drugs 32, 313 (1986).

Sertraline, 1-(3,4-dichlorophenyl)-4-methylaminotetralin, is disclosedin U.S. Pat. No. 4,536,518.

Paroxetine,trans-(−)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine,may be found in U.S. Pat. Nos. 3,912,743 and 4,007,196. Reports of thedrug's activity are in Lassen, Eur. J. Pharmacol. 47, 351 (1978);Hassan, et al., Brit. J. Clin. Pharmacol. 19, 705 (1985); Laursen, etal., Acta Psychiat. Scand. 71, 249 (1985); and Battegay, et al.,Neuropsychobiology 13, 31 (1985).

All of the U.S. patents which have been mentioned above in connectionwith compounds used in the present invention are incorporated herein byreference.

Fluoxetine or duloxetine are the preferred SRI's in pharmaceuticalcompositions combining a compound of formula I and an SRI, and thecorresponding methods of treatment.

It will be understood by the skilled reader that all of the compoundsused in the present invention are capable of forming salts, and that thesalt forms of pharmaceuticals are commonly used, often because they aremore readily crystallized and purified than are the free bases. In allcases, the use of the pharmaceuticals described above as salts iscontemplated in the description herein and often is preferred, and thepharmaceutically acceptable salts of all of the compounds are includedin the names of them.

The dosages of the drugs used in the present combination must, in thefinal analysis, be set by the physician in charge of the case, usingknowledge of the drugs, the properties of the drugs in combination asdetermined in clinical trials, and the characteristics of the subject,including diseases other than that for which the physician is treatingthe subject. General outlines of the dosages, and some preferred humandosages, can and will be provided here. Dosage guidelines for some ofthe drugs will first be given separately; in order to create a guidelinefor any desired combination, one would choose the guidelines for each ofthe component drugs.

Fluoxetine: from about 1 to about 80 mg, once/day; preferred, from about10 to about 40 mg once/day; preferred for bulimia andobsessive-compulsive disease, from about 20 to about 80 mg once/day;

Duloxetine: from about 1 to about 30 mg once/day; preferred, from about5 to about 20 mg once/day;

Venlafaxine: from about 10 to about 150 mg once-thrice/day; preferred,from about 25 to about 125 mg thrice/day;

Milnacipran: from about 10 to about 100 mg once-twice/day; preferred,from about 25 to about 50 mg twice/day;

Citalopram: from about 5 to about 50 mg once/day; preferred, from about10 to about 30 mg once/day;

Fluvoxamine: from about 20 to about 500 mg once/day; preferred, fromabout 50 to about 300 mg once/day;

Paroxetine: from about 5 to about 100 mg once/day; preferred, from about50 to about 300 mg once/day.

In more general terms, one would create a combination of the presentinvention by choosing a dosage of SRI according to the spirit of theabove guideline, and choosing a dosage of the compound of formula I inthe ranges taught above.

The adjunctive therapy of the present invention is carried out byadministering a SRI together with a compound of formula I in any mannerwhich provides effective levels of the two compounds in the body at thesame time. All of the compounds concerned are orally available and arenormally administered orally, and so oral administration of theadjunctive combination is preferred. They may be administered together,in a single dosage form, or may be administered separately.

However, oral administration is not the only route or even the onlypreferred route. For example, transdermal administration may be verydesirable for patients who are forgetful or petulant about taking oralmedicine. One of the drugs may be administered by one route, such asoral, and the other may be administered by the trans-dermal,percutaneous, intravenous, intramuscular, intranasal or intrarectalroute, in particular circumstances. The route of administration may bevaried in any way, limited by the physical properties of the drugs andthe convenience of the patient and the caregiver.

It is particularly preferred, however, for the adjunctive combination tobe administered as a single pharmaceutical composition, and sopharmaceutical compositions incorporating both a SRI and a compound offormula I are important embodiments of the present invention. Suchcompositions may take any physical form which is pharmaceuticallyacceptable, but orally usable pharmaceutical compositions areparticularly preferred. Such adjunctive pharmaceutical compositionscontain an effective amount of each of the compounds, which effectiveamount is related to the daily dose of the compounds to be administered.Each adjunctive dosage unit may contain the daily doses of bothcompounds, or may contain a fraction of the daily doses, such asone-third of the doses. Alternatively, each dosage unit may contain theentire dose of one of the compounds, and a fraction of the dose of theother compound. In such case, the patient would daily take one of thecombination dosage units, and one or more units containing only theother compound. The amounts of each drug to be contained in each dosageunit depends on the identity of the drugs chosen for the therapy, andother factors such as the indication for which the adjunctive therapy isbeing given.

As stated above, the benefit of the adjunctive therapy is its ability toaugment the increase in availability of serotonin, norepinephrine anddopamine caused by the SRI compounds, resulting in improved activity intreating the various conditions described below in detail. The increasein availability of serotonin is particularly important and is apreferred aspect of the invention. Further, the invention provides amore rapid onset of action than is usually provided by treatment withthe SRI alone.

Preferred pathological conditions to be treated by the methods disclosedherein include depression, bulimia, obsessive-compulsive disease andobesity. Another preferred condition more specific to combinationsincluding preferably duloxetine but also venlafaxine and milnacipran isurinary incontinence.

Depression in its many variations has recently become much more visibleto the general public than it has previously been. It is now recognizedas an extremely damaging disorder, and one that afflicts a surprisinglylarge fraction of the human population. Suicide is the most extremesymptom of depression, but millions of people, not quite so drasticallyafflicted, live in misery and partial or complete uselessness, andafflict their families as well by their affliction. The introduction offluoxetine was a breakthrough in the treatment of depression, anddepressives are now much more likely to be diagnosed and treated thanthey were only a decade ago. Duloxetine is in clinical trials for thetreatment of depression and is likely to become a marketed drug for thepurpose.

Depression is often associated with other diseases and conditions, orcaused by such other conditions. For example, it is associated withParkinson's disease; with HIV; with Alzheimer's disease; and with abuseof anabolic steroids. Depression may also be associated with abuse ofany substance, or may be associated with behavioral problems resultingfrom or occurring in combination with head injuries, mental retardationor stroke. Depression in all its variations is a preferred target oftreatment with the present adjunctive therapy method and compositions.

Obsessive-compulsive disease appears in a great variety of degrees andsymptoms, generally linked by the victim's uncontrollable urge toperform needless, ritualistic acts. Acts of acquiring, ordering,cleansing and the like, beyond any rational need or rationale, are theoutward characteristic of the disease. A badly afflicted subject may beunable to do anything but carry out the rituals required by the disease.Fluoxetine is approved in the United States and other countries for thetreatment of obsessive-compulsive disease and has been found to beeffective.

Obesity is a frequent condition in the American population. It has beenfound that fluoxetine will enable an obese subject to lose weight, withthe resulting benefit to the circulation and heart condition, as well asgeneral well being and energy.

Urinary incontinence is classified generally as stress or urgeincontinence, depending on whether its root cause is the inability ofthe sphincter muscles to keep control, or the overactivity of thebladder muscles. Duloxetine controls both types of incontinence, or bothtypes at once, and so is important to the many who suffer from thisembarrassing and disabling disorder.

The present treatment methods are useful for treating many otherdiseases, disorders and conditions as well, as set out below. In manycases, the diseases to be mentioned here are classified in theInternational Classification of Diseases, 9th Edition (ICD), or in theDiagnostic and Statistical Manual of Mental Disorders, 3rd VersionRevised, published by the American Psychiatric Association (DSM). Insuch cases, the ICD or DSM code numbers are supplied below for theconvenience of the reader.

depression, ICD 296.2 & 296.3, DSM 296, 294.80, 293.81, 293.82, 293.83,310.10, 318.00, 317.00

migraine

pain, particularly neuropathic pain

bulimia, ICD 307.51, DSM 307.51

premenstrual syndrome or late luteal phase syndrome, DSM 307.90

alcoholism, ICD 305.0, DSM 305.00 & 303.90

tobacco abuse, ICD 305.1, DSM 305.10 & 292.00

panic disorder, ICD 300.01, DSM 300.01 & 300.21

anxiety, ICD 300.02, DSM 300.00

post-traumatic syndrome, DSM 309.89

memory loss, DSM 294.00

dementia of aging, ICD 290

social phobia, ICD 300.23, DSM 300.23

attention deficit hyperactivity disorder, ICD 314.0

disruptive behavior disorders, ICD 312

impulse control disorders, ICD 312, DSM 312.39 & 312.34

borderline personality disorder, ICD 301.83, DSM 301.83

chronic fatigue syndrome

premature ejaculation, DSM 302.75

erectile difficulty, DSM 302.72

anorexia nervosa, ICD 307.1, DSM 307.10

disorders of sleep, ICD 307.4

autism

mutism

trichotillomania

Further, the compounds of formula I are useful for alleviating thesymptoms of smoking cessation or nicotine withdrawal when administeredalone or in combination with a serotonin reuptake inhibitor. The SRI'sto be used in this treatment method, and the administration methods andformulations, are as described above. The use of the present compoundswith SRI's in subjects striving to stop use of tobacco or nicotineprovides alleviation of the usual painful and damaging symptoms of suchsubjects, including nervousness, irritability, craving, excessiveappetite, anxiety, depression in many forms, inability to concentrate,and the like. The control or elimination of weight gain in the subjectundergoing withdrawal from or reduction of tobacco or nicotine use is aparticularly valuable and preferred benefit of the use of a presentcompound in combination with an SRI.

Therapeutic Applications The compounds of formula I are useful for otherimportant therapeutic purposes, as well as in combination with SRIs andin nicotine withdrawal or smoking cessation cases. In particular, thecompounds are valuable for binding, blocking or modulating theserotonin-1A receptor, for binding, blocking or modulating theserotonin-2A receptor, and for the treatment or prophylaxis ofconditions caused by or influenced by defective function of thesereceptors. In particular, the compounds are useful for antagonism at theserotonin-1A receptor and the serotonin-2A receptor, and accordingly areused for the treatment or prevention of conditions caused by or affectedby excessive activity of these receptors.

More particularly, the compounds of formula I are useful in thetreatment of anxiety, depression, hypertension, cognitive disorders,psychosis, sleep disorders, gastric motility disorders, sexualdysfunction, brain trauma, memory loss, appetite disorders and obesity,substance abuse, obsessive-compulsive disease, panic disorder andmigraine.

Anxiety and its frequent concomitant, panic disorder, may beparticularly mentioned in connection with the present compounds. Thesubject is carefully explained by the Diagnostic and Statistical Manualof Mental Disorders, published by the American Psychiatric Association,which classifies anxiety under its category 300.02. It is understoodthat the following specific disorders are also included within themethod of the present invention; “generalized anxiety disorder”, “panicdisorder”, “social phobia”, “social anxiety”, “post traumatic stressdisorder”, “acute stress disorder”, “anxiety due to general medicalcondition”, “substance induced anxiety disorder”, and “anxiety disordernot otherwise specified”. A further particularly noted disorder isdepression and the group of depression-related disorders, which arediscussed above in the discussion of adjunctive therapy with SRIs.Further included within the scope of the term anxiety is “socialfunctioning” as appreciated by one of ordinary skill in the art.

The unique combination of pharmacological properties possessed by thecompounds of formula I permit those compounds to be used in a method ofsimultaneously treating anxiety and depression. The anxiety portion ofthe combined syndrome is believed to be attacked by the 5HT-1_(A)receptor-affecting property of the compounds, and the depression portionof the condition is believed to be addressed by the reuptake inhibitionproperty. Thus, administration of an effective amount, which isdetermined in an analogous manner as discussed hereinabove, of acompound of formula I, will provide a method of simultaneously treatinganxiety and depression.

Pharmaceutical Compositions

It is customary to formulate pharmaceuticals for administration, toprovide control of the dosage and stability of the product in shipmentand storage, and the usual methods of formulation are entirelyapplicable to the compounds of formula I. Such compositions, comprisingat least one pharmaceutically acceptable carrier, are valuable and novelbecause of the presence of the compounds of formula I therein. Althoughpharmaceutical chemists are well aware of many effective ways toformulate pharmaceuticals, which technology is applicable to the presentcompounds, some discussion of the subject will be given here for theconvenience of the reader.

The usual methods of formulation used in pharmaceutical science and theusual types of compositions may be used according to the presentinvention, including tablets, chewable tablets, capsules, solutions,parenteral solutions, intranasal sprays or powders, troches,suppositories, transdermal patches and suspensions. In general,compositions contain from about 0.5% to about 50% of the compound intotal, depending on the desired dose and the type of composition to beused. The amount of the compound, however, is best defined as theeffective amount, that is, the amount of each compound which providesthe desired dose to the subject in need of such treatment. The activityof the compounds do not depend on the nature of the composition, so thecompositions are chosen and formulated solely for convenience andeconomy. Any compound may be formulated in any desired form ofcomposition. Some discussion of different compositions will be provided,followed by some typical formulations.

Capsules are prepared by mixing the compound with a suitable diluent andfilling the proper amount of the mixture in capsules. The usual diluentsinclude inert powdered substances such as starch of many differentkinds, powdered cellulose, especially crystalline and microcrystallinecellulose sugars such as fructose, mannitol and sucrose, grain floursand similar edible powders.

Tablets are prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant is necessary in a tablet formulation to prevent the tabletand punches from sticking in the die. The lubricant is chosen from suchslippery solids as talc, magnesium and calcium stearate, stearic acidand hydrogenated vegetable oils.

Tablet disintegrators are substances which swell when wetted to break upthe tablet and release the compound. They include starches, clays,celluloses, algins and gums. More particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used, as well assodium lauryl sulfate.

Enteric formulations are often used to protect an active ingredient fromthe strongly acidic contents of the stomach. Such formulations arecreated by coating a solid dosage form with a film of a polymer which isinsoluble in acidic environments, and soluble in basic environments.Exemplary films are cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate.

Tablets are often coated with sugar as a flavor and sealant, or withfilm-forming protecting agents to modify the dissolution properties ofthe tablet. The compounds may also be formulated as chewable tablets, byusing large amounts of pleasant-tasting substances such as mannitol inthe formulation, as is now well-established practice. Instantlydissolving tablet-like formulations are also now frequently used toassure that the subject consumes the dosage form, and to avoid thedifficulty in swallowing solid objects that bothers some subjects.

When it is desired to administer the combination as a suppository, theusual bases may be used. Cocoa butter is a traditional suppository base,which may be modified by addition of waxes to raise its melting pointslightly. Water-miscible suppository bases comprising, particularly,polyethylene glycols of various molecular weights are in wide use, also.

Transdermal patches have become popular recently. Typically theycomprise a resinous composition in which the drugs will dissolve, orpartially dissolve, which is held in contact with the skin by a filmwhich protects the composition. Many patents have appeared in the fieldrecently. Other, more complicated patch compositions are also in use,particularly those having a membrane pierced with pores through whichthe drugs are pumped by osmotic action.

The following typical formulae are provided for the interest andinformation of the pharmaceutical scientist.

Formulation 1 Hard gelatin capsules are prepared using the followingingredients: Quantity (mg/capsule) Example #1  20 mg Starch dried 200 mgMagnesium stearate  10 mg Total 230 mg

Formulation 2 Composition of 40 mg Capsules - Total (net) 230 mg Amountmg/ Composition Ingredient capsule % by weight4-(7-benzo(b)thiophene-1,2,3,6- 40.00 17.55tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl) butan-1-one Sodium LaurylSulfate 1.84 0.80 Magnesium Stearate Vegetable 1.15 0.50 Starch FlowablePowder 187.01 81.15

Add the4-(7-benzo(b)thiophene-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-one,sodium lauryl sulfate and starch flowable powder (50% of total amount)through a #20 security screen into a stainless steel container. Mix thecomponents in an appropriate powder mixer, such as a Twin Shell blender.Then pass the components through a 0.610 screen using a mill, such as aQuadro Comil, and chase the balance of the starch through the mill intothe stainless steel container. Move the entire mixture to the powdermixer and mix for 30 minutes. Then add the magnesium stearate through a#40 screen into the powder mixer and mix for 10 minutes. Then fill theappropriate amount into gelatin capsules No. 3 using a capsule fillingmachine.

As with any group of structurally related compounds which possess aparticular generic utility, certain groups and configurations arepreferred for compounds of formula I.

With respect to X, compounds of formula I wherein X is O or S arepreferred. With respect to Y, compounds of formula I wherein Y is—C(═O)— or —CH(OH)— are preferred. With respect to R_(1a), R_(1b) andR_(1c), compounds of formula I wherein R_(1a), R_(1b) and R_(1c) are H,F, Cl, Br, OH, C₁-C₄ alkyl or C₁-C₄ alkoxy are preferred. With respectto R₂, compounds of formula I wherein R₂ is H, C₁-C₄ alkyl and—C(═O)NR₇R₈ are preferred. With respect to R₃, compounds of formula Iwherein R₃ is H or methyl are preferred. With respect to R₄, compoundsof formula I wherein R₄ is phenyl, naphthyl, cyclopentyl, cyclohexyl,2-pyridyl, 3-pyridyl or 4-pyridyl are preferred. With respect to R₅,compounds of formula I wherein R₅ is phenyl, naphthyl, cyclopentyl,cyclohexyl, 2-pyridyl, 3-pyridyl or 4 pyridyl are preferred. Withrespect to the piperidine ring on formula I, the following substitutionsfor R_(6a) and R_(6b) are preferred:

We claim:
 1. A compound of the formula:

wherein: X is O, S, NR, S(═O), or S(═O)₂; Y is —C(═O)—, —CH(OH)—, —CH₂—,—C(═NOR), CHNR₇R, S, SO, or SO₂; ------- represents a single or a doublebond; n is 1, 2, 3 or 4; R is H or C₁-C₆ alkyl; R_(1a), R_(1b), R_(1c)and R₂ are each independently H, F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, —NR₇R₈,—C(═O)NR₇R₈, —NR₇C(═O)R₈, CN or phenyl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl,NO₂, NH₂, or CN; R₃ is H, OH, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkyl, C₁-C₆alkoxy, or (C₁-C₆)alkylthio; R₄ is aryl, pyridyl, C₃-C₈ cycloalkyl, arylsubstituted with from 1 to 3 substituents selected from the groupconsisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; or pyridylsubstituted with from 1 to 3 substituents selected from the groupconsisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; R₅ is aryl,pyridyl, C₃-C₈ cycloalkyl, aryl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; or pyridyl substituted withfrom 1 to 3 substituents selected from the group consisting of F, Cl,Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; R_(6a) andR_(6b) are each independently H or C₁-C₃ alkyl; R₇ and R₈ are eachindependently H, C₁-C₆ alkyl, aryl or aryl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl,NO₂, NH₂, or CN; and the pharmaceutically acceptable salts thereof.
 2. Acompound according to claim 1 wherein X is O.
 3. A compound according toclaim 1 wherein X is S.
 4. A compound according to claim 2 wherein R₂ isH.
 5. A compound according to claim 3 wherein R₂ is H.
 6. A compoundaccording to claim 4 wherein n is
 2. 7. A compound according to claim 5wherein n is
 2. 8. A compound according to claim 6 wherein R₃ is H.
 9. Acompound according to claim 7 wherein R₃ is H.
 10. A compound accordingto claim 8 wherein R₄ is 2-pyridyl.
 11. A compound according to claim 9wherein R₄ is 2-pyridyl.
 12. A compound according to claim 10 wherein----- a double bond.
 13. A compound according to claim 11 wherein -----is a double bond.
 14. A compound according to claim 12 wherein Y is—C(═O)—.
 15. A compound according to claim 13 wherein Y is —C(═O)—. 16.A compound according to claim 2 wherein R₃ is methyl.
 17. A compoundaccording to claim 3 wherein R₃ is methyl.
 18. A compound which is4-(7-benzo(b)thiophene-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-oneand the pharmaceutically acceptable salts thereof.
 19. A compound whichis4-(7-benzo(b)thiophene-1,2,3,6-tetrahydropyridyl)-1-cyclohexyl-2-(2-pyridyl)butan-1-one.20. A compound of the formula:

and the pharmaceutically acceptable salts thereof.
 21. A compound of theformula:


22. A pharmaceutical composition comprising an effective amount of acompound according to claim 1 in combination with a pharmaceuticallyacceptable carrier, diluent or excipient.
 23. A method of inhibiting thereuptake of serotonin and antagonizing the 5-HT_(1A) receptor whichcomprises administering to a subject in need of such treatment aneffective amount of a compound of the formula

wherein: X is O, S, NR, S(═O), or S(═O)₂; Y is —C(═O)—, —CH(OH)—, —CH₂—,—C(═NOR), CHNR₇R, S, SO, or SO₂; ------- represents a single or a doublebond; n is 1, 2, 3 or 4; R is H or C₁-C₆ alkyl; R_(1a), R_(1b), R_(1c)and R₂ are each independently H, F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, —NR₇R₈,—C(═O)NR₇R₈, —NR₇C(═O)R₈, CN or phenyl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl,NO₂, NH₂, or CN; R₃ is H, OH, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkyl, C₁-C₆alkoxy, or (C₁-C₆)alkylthio; R₄ is aryl, pyridyl, C₃-C₈ cycloalkyl, arylsubstituted with from 1 to 3 substituents selected from the groupconsisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; or pyridylsubstituted with from 1 to 3 substituents selected from the groupconsisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; R₅ is aryl,pyridyl, C₃-C₈ cycloalkyl, aryl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; or pyridyl substituted withfrom 1 to 3 substituents selected from the group consisting of F, Cl,Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; R_(6a), andR_(6b) are each independently H or C₁-C₃ alkyl; R₇ and R₈ are eachindependently H, C₁-C₆ alkyl, aryl or aryl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl,NO₂, NH₂, or CN; and the pharmaceutically acceptable salts thereof. 24.A method of potentiating the action of a serotonin reuptake inhibitorcomprising administering to a subject in of such treatment a compoundformula

wherein: X is O, S, NR, S(═O), or S(═O)₂; Y is —C(═O)—, —CH(OH)—, —CH₂—,—C(═NOR), CHNR₇R, S, SO, or SO₂; ------- represents a single or a doublebond; n is 1, 2, 3 or 4; R is H or C₁-C₆ alkyl; R_(1a), R_(1b), R_(1c)and R₂ are each independently H, F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, —NR₇R₈,—C(═O)NR₇R₈, —NR₇C(═O)R₈, CN or phenyl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl,NO₂, NH₂, or CN; R₃ is H, OH, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkyl, C₁-C₆alkoxy, or (C₁-C₆)alkylthio; R₄ is aryl, pyridyl, C₃-C₈ cycloalkyl, arylsubstituted with from 1 to 3 substituents selected from the groupconsisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; or pyridylsubstituted with from 1 to 3 substituents selected from the groupconsisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; R₅ is aryl,pyridyl, C₃-C₈ cycloalkyl, aryl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; or pyridyl substituted withfrom 1 to 3 substituents selected from the group consisting of F, Cl,Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; R_(6a) andR_(6b) are each independently H or C₁-C₃ alkyl; R₇ and R₈ are eachindependently H, C₁-C₆ alkyl, aryl or aryl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl,NO₂, NH₂, or CN; and the pharmaceutically acceptable salts thereof. 25.A method of treating depression comprising administering to a subject inneed thereof an effective amount of a compound of formula:

wherein: X is O, S, NR, S(═O), or S(═O)₂; Y is —C(═O)—, —CH(OH)—, —CH—,—C(═NOR), CHNR₇R, S, SO, or SO₂; ------- represents a single or a doublebond; n is 1, 2, 3 or 4; R is H or C₁-C₆ alkyl; R_(1a), R_(1b), R_(1c)and R₂ are each independently H, F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, —NR₇R₈,—C(═O)NR₇R₈, —NR₇C(═O)R₈, CN or phenyl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl,NO₂, NH₂, or CN; R₃ is H, OH, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkyl, C₁-C₆alkoxy, or (C₁-C₆)alkylthio; R₄ is aryl, pyridyl, C₃-C₈ cycloalkyl, arylsubstituted with from 1 to 3 substituents selected from the groupconsisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; or pyridylsubstituted with from 1 to 3 substituents selected from the groupconsisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; R₅ is aryl,pyridyl, C₃-C₈ cycloalkyl, aryl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; or pyridyl substituted withfrom 1 to 3 substituents selected from the group consisting of F, Cl,Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl, NO₂, NH₂, or CN; R_(6a) andR_(6b) are each independently H or C₁-C₃ alkyl; R₇ and R₈ are eachindependently H, C₁-C₆ alkyl, aryl or aryl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkylthio, phenyl,NO₂, NH₂, or CN; and the pharmaceutically acceptable salts thereof.